Aza spiro alkane derivatives as inhibitors of metalloproteases

ABSTRACT

The present invention provides a compound of Formula I or Formula II: 
                         
enantiomer, diastereomer, prodrug, solvate, metabolite, or pharmaceutically acceptable salt thereof, wherein constituent variables are provided herein. The compounds of Formula I and II are modulators of metalloproteases and are useful in treating diseases associated with metalloprotease activity such as arthritis, cancer, cardiovascular disorders, skin disorders, inflammation and allergic conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/204,423, filedJul. 7, 2016, which is a continuation of U.S. Ser. No. 14/092,351, filedNov. 27, 2013, which is a continuation of U.S. Ser. No. 13/184,860,filed Jul. 18, 2011, which is a continuation of U.S. Ser. No.12/327,313, filed Dec. 3, 2008, which is a continuation of U.S. Ser. No.10/831,265, filed Apr. 23, 2004, which claims the benefit of U.S. Ser.No. 60/466,159, filed Apr. 24, 2003, and U.S. Ser. No. 60/534,501, filedJan. 6, 2004, the disclosures of each of which are incorporated hereinby reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to aza spiro alkane compounds which areuseful in treating diseases, pathologic conditions and disordersassociated with metalloprotease activity, including activity ofsheddases and adamalysins (ADAMs).

BACKGROUND OF THE INVENTION

Most tissues exist in a highly regulated dynamic equilibrium wherein newtissue is formed and existing tissue is degraded and eliminated. Thedegradation of the extracellular matrix (ECM), including connectivetissue and basement membranes, is effected by the metalloproteinaseswhich are released from connective tissue and invading inflammatorycells. Excessive unregulated activity of these enzymes can result inundesirable tissue destruction and their activity is regulated at thetranscription level, by controlled activation of the latent proenzymeand, after translation, by intracellular specific inhibitory factorssuch as TIMP (“Tissue Inhibitors of MetalloProteinase”) or by moregeneral proteinase inhibitors such as α2-macroglobulins.

Several structurally related metalloproteases (MPs) are known to play animportant role in the breakdown of structural proteins. Thesemetalloproteases typically act on the intercellular matrix, and thus areinvolved in tissue breakdown and remodeling. Such proteins have beenreferred to as metalloproteases or MPs. There are several differentfamilies of MPs, classified by sequence homology. Several families ofknown MPs, as well as examples thereof, are disclosed in the art.

These MPs include Matrix-Metallo Proteases [MMPs], zincmetalloproteases, many of the membrane bound metalloproteases, TNFconverting enzymes, angiotensin-converting enzymes (ACEs), disintegrins,including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 Oct. 25,1995), and the enkephalinases. Examples of MPs include human skinfibroblast collagenase, human skin fibroblast gelatinase, human sputumcollagenase, aggrecanse and gelatinase, and human stromelysin.Collagenase, stromelysin, aggrecanase and related enzymes are thought tobe important in mediating the symptomatology of a number of diseases.

Zinc proteases are subdivided according to the primary structure oftheir catalytic sites and include gluzincin, metzincin, inuzincin,carboxypeptidase, and DD carboxypeptidase subgroups (Hooper N M, 1994,FEBS Lett, 354:1-6). The metzincin subgroup is further divided intoserralysins, astacins, matrixins, and adamalysins (Stocker W and Bode W,1995, Curr Opin Struct Biol, 5:383-390).

The matrixins include the matrix metalloproteases, or MMPs. MMPsconstitute a family of structurally similar zinc-containingmetalloproteases, which are involved in the remodeling and degradationof extracellular matrix proteins, both as part of normal physiologicalprocesses and in pathological conditions. For a review see Bode, W etal., 1996, Adv Exp Med Biol, 389:1-11. Connective tissue, extracellularmatrix constituents and basement membranes are the biological materialsthat provide rigidity, differentiation, attachment sites and, in somecases, elasticity to biological systems. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin that form the scaffold for all human tissues. Under normalconditions, connective tissue turnover and/or repair processes arecontrolled and in equilibrium. The loss of this balance, for whateverreason, leads to a number of disease states. Inhibition of the enzymesresponsible loss of equilibrium provides a control mechanism for thistissue decomposition and, therefore, a treatment for these diseases. Theuncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions.

Besides a role in the regulation of extracellular matrix, there is alsoevidence to suggest that MMPs mediate the migration of inflammatorycells into tissues (Moscatelli D and Rifkin D B, 1988, Biochim BiophysActa, 948: 67-85). Several reports have demonstrated that various MMPscan activate a variety of important non-matrix proteins, includingcytokines, chemokines, integrins, and antimicrobial peptides (see ParksW C, 2002, J Clin Invest, 110:613-4). Many of the human MMPs are overexpressed in human tumors and are associated with peritumor tissuedegradation and metastasis formation. Another important function ofcertain MMPs is to activate various enzymes, including other MMPs, bycleaving the pro-domains from their protease domains. Thus some MMPs actto regulate the activities of other MMPs, so that over-production of oneMMP may lead to excessive proteolysis of extracellular matrix byanother. It has also been reported that MMPs can cleave and therebyinactivate the endogenous inhibitors of other proteinases such aselastase (Winyard P G et al., 1991, FEBS Letts, 279: 91-94). Inhibitorsof MMPs could thus influence the activity of other destructiveproteinases by modifying the level of their endogenous inhibitors. Inaddition, increasing or maintaining the levels of an endogenous oradministered serine protease inhibitor supports the treatment andprevention of diseases such as emphysema, pulmonary diseases,inflammatory diseases and diseases of aging such as loss of skin ororgan stretch and resiliency. Thus, MMPs should not be viewed solely asproteinases of ECM catabolism, but rather as extracellular processingenzymes involved in regulating cell-cell and cell-ECM signaling events.

The adamalysins include the reprolysins, snake venom metalloproteasesand the ADAMs. The ADAMs (a disintegrin and metalloprotease domain) area family of type I transmembrane glycoproteins that are important indiverse biologic processes, such as cell adhesion and the proteolyticshedding of cell surface receptors. ADAM family members have beenidentified from mammalian and nonmammalian sources, including Xenopus,Drosophila, and Caenorhabditis elegans. Members of the family have amodular design, characterized by the presence of metalloprotease andintegrin receptor-binding activities, and a cytoplasmic domain that inmany family members specifies binding sites for varioussignal-transducing proteins. The ADAMs family has been implicated in thecontrol of membrane fusion, cytokine, growth factor and growth factorreceptor shedding, and cell migration, as well as processes such asmuscle development, fertilization, neurogenesis, and cell fatedetermination. Loss of regulation can lead to disease and pathology.Pathologies such as infertility, inflammation and cancer have been shownto involve ADAMs family members. For a review, see Wolfsberg T G andWhite J M, 1998, ADAM metalloproteinases. In Handbook of ProteolyticEnzymes (Barrett A J, Rawlings N D and Woessner J F eds), p. 1310-1313,Academic Press, London as well as Seals D F and Courtneidge S A, 2003,Genes and Development, 17:7-30.

Some specific examples of important ADAM metalloproteases include theTNFα-converting enzyme, TACE or ADAM17, that is currently an importanttarget for anti-inflammatory drugs (Moss M L et al., 2001, Drug DiscovToday, 6:417-426 and Black R A, 2002, Int J Biochem Cell Biol, 34:1-5).Other members of the family are also likely to be good therapeutictargets. ADAM8 has been reported to be expressed almost exclusively incells of the immune system, particularly B-cells, monocytes, eosinophilsand granulocytes. ADAM8 therefore represents a therapeutic target forhuman immunological-based diseases. ADAM15 is found in human aorticsmooth muscle and cultured umbilical vein endothelial cells. WhileADAM15 is not expressed in normal blood vessels, it has been detected indeveloping atherosclerotic lesions (Herren B et al., 1997, FASEB J,11:173-180), and has also been shown to be upregulated in osteoarthriticversus normal human cartilage (Bohm B B et al., 1999, Arthritis Rheum,42:1946-1950). Thus ADAM15 may play a role in atherosclerosis andcartilage degeneration diseases. The lymphocyte-specific expression ofthe ADAM28 suggests that it may have an important immunologicalfunction.

Excessive production of IgE is believed to be a major mediator ofallergic responses. CD23, the low affinity receptor for IgE, is subjectto ADAM type metalloprotease-dependent proteolytic release of solubleextracellular fragments, which have been shown to cause upregulation ofIgE production and induction of inflammatory cytokines (see Novak N etal, 2001, Curr Opin Immunol, 13:721-726 and Mayer R J et al., 2002,Inflamm Res, 51:85-90). Increased levels of soluble CD23 have beenobserved in allergic asthma, in chronic B-lymphocytic leukemia and inrheumatoid arthritis. Inhibition of the enzyme(s) responsible for CD23processing may offer a therapeutic approach for the treatment of variousimmune based diseases. ADAM metalloproteases also appear to beresponsible for the release or shedding of soluble receptors (forexample, CD30 and receptors for TNF), adhesion molecules (for example,L-selectin, ICAM-1, fibronectin), growth factors and cytokines (forexample Fas ligand, TGF-α, EGF, HB-EGF, SCF IL-6, IL-1, TSH and M-CSF),and growth factor receptors (for example EGFR family members, such asHer-2 and Her-4, which have been implicated in the pathogenesis ofdifferent types of cancer (Yarden Y and Sliwkowski M X, 2001, NatureReviews 2:127-137). For example, Her-2 is over expressed in 25-30% ofhuman breast cancers and is associated with an increased risk of relapseand death (Slamon D J et al, 1987, Science, 235:177-182). ADAM17 hasrecently been shown to be critical for the regulated shedding of Her-4(Rio C et al, 2000, J Biol Chem, 275:10379-10387). The proteaseresponsible for Her-2 cleavage, known as Her-2 sheddase, is an unknownMMP that may also be a member of the ADAM family (Codony-Servat J et al,1999, Cancer Res 59:1196-1201). Modulation of this activity mighttherefore have an important role in the modulation of human disease. Fora review of the sheddase activity of ADAMs see Moss M L and Lambert M H,2002, Essays Biochem, 38:141-153.

ADAM-TS proteases have been identified as members of the ADAM family.These proteins are novel in that they contain unique thrombospondin (TS)type I motifs in addition to some of the structurally conserved domainsof other ADAM family members. The ADAMTSs are also distinguished fromthe ADAMs by their lack of cysteine-rich, EGF-like, transmembrane, andcytoplasmic domains. ADAM-TS proteins have also been shown to beassociated with a number of pathological or human disease states. Forexample, ADAMTS-1 is a tumor-selective gene expressed in colon tumorcells and is also an inflammation-associated protein. A human orthologof ADAMTS-1, known as METH-1, and the related protein METH-2 have beenrecently shown to have antiangiogenic activity, and these or otherADAMTS family members may play important roles in regulating vasculardevelopment. ADAMTS-2 has been implicated in the normal development ofthe skin. This enzyme was long known as procollagen N-proteinase, aproteinase that proteolytically removes amino peptides in the processingof type I and type II procollagens to collagens, and it was shown to bedeficient in the skin of individuals with the inherited connectivetissue disorder type VIIC Ehlers-Danros syndrome. ADAMTS-4 and ADAMTS-11are known as aggrecanase-1 and -2 because of their ability to cleavespecific sites in aggrecan, a proteoglycan that maintains the mechanicalproperties of cartilage. Progressive degradation and depletion ofaggrecan has been implicated in degenerative joint diseases such asosteoarthritis and inflammatory joint diseases such as rheumatoidarthritis. For a review of the ADAM-TS metalloproteases see Tang B L,2001, Int J Biochem Cell Biol, 33:33-44 and Kaushal G P and S V Shah,2000, J Clin Invest 105:1335-1337.

The metalloproteases are one of the older classes of proteinases and arefound in bacteria, fungi as well as in higher organisms. Many enzymescontain the sequence HEXXH, which provides two histidine ligands for thezinc whereas the third ligand is either a glutamic acid (thermolysin,neprilysin, alanyl aminopeptidase) or a histidine (astacin). Otherfamilies exhibit a distinct mode of binding of the Zn atom.Metalloproteases have therefore been isolated from a number ofprokaryotic and eukaryotic sources. Acidic metalloproteases have beenisolated from broad-banded copperhead and rattlesnake venoms. Neutralmetalloproteases, specifically those having optimal activity at neutralpH have, for example, been isolated from Aspergillus sojae. Alkalinemetalloproteases, for example, have been isolated from Pseudomonasaeruginosa and the insect pathogen Xenorhabdus luminescens. Inhibitionof microbial metalloproteases may lead to growth inhibition andrepresent an antibiotic strategy. Inhibition of metalloproteasesassociated with snake venom or insect toxicity may also lead to newtherapeutic strategies.

Potential therapeutic indications of MP inhibitors have been discussedin the literature. See for example, U.S. Pat. No. 6,500,847 (BayerCorporation), U.S. Pat. No. 6,268,379 (DuPont Pharmaceuticals Company),U.S. Pat. No. 5,968,795 (Bayer Corporation), U.S. Pat. No. 5,892,112(Glycomed Incorporated and The University of Florida), and U.S. Pat. No.5,872,152 (British Biotech Pharmaceuticals Limited). Some examples whereinhibition of metalloprotease activity would be of benefit include: a)osteoarthritis, b) rheumatic diseases and conditions such as autoimmunedisease, rheumatoid arthritis, c) septic arthritis, d) cancer includingtumor growth, tumor metastasis and angiogenesis, e) periodontaldiseases, f) corneal, epidermal or gastric ulceration (ulcerativeconditions can result in the cornea as the result of alkali burns or asa result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpessimplex and vaccinia viruses), g) proteinuria, h) various cardiovascularand pulmonary diseases such as atherosclerosis, thrombotic events,atheroma, hemodynamic shock, unstable angina, restenosis, heart failure,i) aneurysmal diseases including those of the aorta, heart or brain, j)birth control, k) dystrophobic epidermolysis bullosa, l) degenerativecartilage loss following traumatic joint injury, m) osteopenias andother diseases of abnormal bone loss including osteoporosis, n) temperomandibular joint disease, o) pulmonary diseases such as chronicobstructive pulmonary disease, p) demyelinating diseases of the nervoussystem such as multiple sclerosis, q) metabolic diseases includingdiabetes (with enhanced collagen degradation) and obesity mediated byinsulin resistance, macular degeneration and diabetic retinopathymediated by angiogenesis, cachexia, premature skin aging, r) impairedwound healing including burns, s) decubital ulcers, t) acute and chronicneurodegenerative disorders including stroke, spinal cord and traumaticbrain injury, amyotrophic lateral sclerosis, cerebral amyloidangiopathy, CNS injuries in AIDS, Parkinson's disease, Alzheimer'sdisease, Huntington's diseases, prion diseases, myasthenia gravis, andDuchenne's muscular dystrophy, u) pain, v) autoimmune encephalomyelitisand w) diseases linked to TNFα production and/or signaling such as awide variety of inflammatory and/or immunomodulatory diseases, includingacute rheumatic fever, rheumatoid arthritis, multiple sclerosis,allergy, periodontal diseases, hepatitis, bone resorption, sepsis, gramnegative sepsis, septic shock, endotoxic shock, toxic shock syndrome,systemic inflammatory response syndrome, inflammatory bowel diseasesincluding Crohn's disease and ulcerative colitis, Jarisch-Herxheimerreactions, asthma, adult respiratory distress syndrome, acute pulmonaryfibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases,silicosis, coal worker's pneumoconiosis, alveolar injury, hepaticfailure, liver disease during acute inflammation, severe alcoholichepatitis, malaria including Plasmodium falciparum malaria and cerebralmalaria, congestive heart failure, damage following heart disease,arteriosclerosis including atherosclerosis, Alzheimer's disease, acuteencephalitis, brain injury, pancreatitis including systemiccomplications in acute pancreatitis, impaired wound healing and immuneresponses in infection inflammation and cancer, myelodysplasticsyndromes, systemic lupus erythematosus, biliary cirrhosis, non-insulindependent diabetes mellitus, bowel necrosis, psoriasis, cachexia andanorexia, radiation injury, and toxicity following administration ofmonoclonal antibodies such as OKT3, host-versus-graft reactionsincluding ischemia reperfusion injury and allograft rejections includingthose of the kidney, liver, heart, and skin, lung allograft rejectionincluding chronic lung allograft rejection (obliterative bronchitis), aswell as complications due to total hip replacement, infectious diseasesincluding Mycobacterial infection, meningitis, Helicobacter pyloriinfection during peptic ulcer disease, Chaga's disease resulting fromTrypanosoma cruzi infection, effects of Shiga-like toxin resulting fromE. coli infection, the effects of enterotoxin A resulting fromStaphylococcus infection, meningococcal infection, and infections fromBorrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenzavirus, Sendai virus, Theiler's encephalomyelitis virus, and the humanimmunodeficiency virus (HIV). Defective injury repair processes alsooccur. This can produce improper wound healing leading to weak repairs,adhesions and scarring. These latter defects can lead to disfigurementand/or permanent disabilities as with post-surgical adhesions.

Matrix metalloprotease inhibitors are useful in treating diseasescaused, at least in part, by breakdown of structural proteins. Though avariety of inhibitors have been prepared, there is a continuing need forpotent matrix metalloprotease inhibitors useful in treating suchdiseases. Applicants have found that, surprisingly, the compounds of thepresent invention are potent metalloprotease inhibitors.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I or II:

or enantiomer, diastereomer, prodrug, solvate, metabolite, orpharmaceutically acceptable salt thereof, wherein constituent membersare provided hereinbelow.

The present invention further provides compositions comprising acompound of Formula I or II and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating a diseaseassociated with unwanted metalloprotease activity.

The present invention further provides a method for treating a diseasemodulated by a metalloprotease in a mammalian subject, wherein thedisease is selected from the group consisting of arthritis, cancer,cardiovascular disorders, skin disorders, inflammation and allergicconditions.

The present invention further provides a method for treating cancer,including but not limited to breast cancer, in a mammal.

The present invention further provides a method of inhibitingpathological changes mediated by elevated levels of matrixmetalloproteases in mammals comprising administering to said mammal inneed thereof a therapeutically effective amount of a compound of theinvention.

The present invention further provides a method for treating a diseaseassociated with unwanted TNF-α converting enzyme activity.

The present invention further provides a method for treating a diseaseassociated with unwanted matrix metalloprotease activity wherein saidmatrix metalloprotease is selected from the group consisting of MMP12,MMP14, MMP3, MMP2, and MMP9 in a mammalian subject.

The present invention further provides a method for treating a diseaseassociated with unwanted activity of Her-2 sheddase, growth factorsheddases, or cytokine sheddases in a mammalian subject.

The present invention further provides a method for treating a diseaseassociated with activity of Her-2 sheddase in a mammal.

The present invention further provides a method for treating a diseaseassociated with unwanted ADAM10, ADAM15, or ADAM17 activity in amammalian subject.

DETAILED DESCRIPTION

The instant invention provides, inter alia, compounds and pharmaceuticalcompositions of matter for treating pathological conditions which areassociated with metalloprotease activity such as the rapid, unregulatedbreakdown of extracellular matrix tissue by MMPs including, but notlimited to, MMP 12 and MMP 13. Some of these conditions includerheumatoid arthritis, osteoarthritis, septic arthritis, corneal,epidermal or gastric ulceration; periodontal disease, proteinuria,coronary thrombosis associated with atherosclerotic plaque rupture andbone disease. The compounds of the invention are also useful fortreating cancer including, for example, tumor metastasis andangiogenesis which also appears to be associated withe metalloproteaseactivity. Also, since the cycle of tissue damage and response isassociated with a worsening of the disease state, limitingmetalloprotease-induced tissue damage due to elevated levels of theproteinases with the compounds of the instant invention can be agenerally useful therapeutic approach to many of these debilitatingdiseases and others. The compounds of the invention are also inhibitorsTNFα converting enzyme and sheddases including Her-2 sheddase and HB-EGFsheddase and other growth factor and cytokine sheddases.

The present invention provides a compound of Formula I or II:

or enantiomer, diastereomer, prodrug, solvate, metabolite, orpharmaceutically acceptable salt thereof, wherein:

A is CWOH, CWNHOH, CWNHOR₅, N(OH)CHO, N(OH)CWR₆, SH, SR₇ or hydantoinyl;

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), O(C═W)NR₈, O, N, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n), C(O)(CR_(d)R_(f))_(n), or combinationsthereof;

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), O(C═W)NR₈, O, N, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n), C(O)(CR_(d)R_(f))_(n) or combinations thereof;

D is oxygen or sulfur;

X is absent, (CH₂)_(j), C₁₋₁₀ alkylene substituted with 0 to 3 R_(a),C₂₋₁₀ alkenylene substituted with 0 to 2 R_(a), N, O, NR_(b), S(O)_(m),C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O, OC(O),S(O)_(m)NR_(b), NR_(b)S(O)_(m), NR_(b)S(O)_(m)NR_(b),(CR_(d)R_(f))_(j)NR_(b), NR_(b)(CR_(d)R_(f))_(j), or combinationsthereof;

Y is absent, (CH₂)_(j), C₁₋₁₀ alkylene substituted with 0 to 3 R_(a),C₂₋₁₀ alkenylene substituted with 0 to 2 R_(a), N, O, NR_(b), S(O)_(m),C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O, OC(O),S(O)_(m)NR_(b), NR_(b)S(O)_(m), NR_(b)S(O)_(m)NR_(b),(CR_(d)R_(f))_(j)NR_(b), NR_(b)(CR_(d)R_(f))_(j), or combinationsthereof;

M is CO or S(O)₁;

U is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), C₂₋₁₀alkenylene substituted with 0 to 2 R_(a), N, O, NR_(b), NR_(b)C(O),NR_(b)C(O)O, NR_(b)C(O)NR_(b), NR_(b)S(O)_(m), NR_(b)S(O)NR_(b) orcombinations thereof;

V is absent, H, C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e) orheterocyclyl substituted with 0-5 R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), C₂₋₁₀alkenylene substituted with 0 to 2 R_(a), N, O, NR_(b)S(O)_(m), C═O,NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O, OC(O), S(O)_(m)NR_(b),NR_(b)S(O)_(m), NR_(b)S(O)NR_(b) or combinations thereof;

V′ is H, C₁₋₈ alkyl, NRbRc, C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e)or heterocyclyl substituted with 0-5 R_(e);

R_(a) and R_(e) are each, independently, H, T, C₁₋₈alkylene-T,C₂₋₈alkenylene-T, C₂₋₆alkynylene-T, C(O)NR_(a)′(CR_(b)′R_(c)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, S(O)_(p)(CR_(b)′R_(c)′)_(r)-T,(CR_(b)′R_(c)′)_(r)—O—(CR_(b)′R_(c)′)_(r)-T, OH, Cl, F, Br, I, CN, NO₂,NR^(I)R^(II), COR^(III), COOR^(IV), OR^(V), CONR^(I)R^(II),NR^(I)CONR^(I)R^(II), OCONR^(I)R^(I), NR^(I)COR^(II), SO₂NR^(I)R^(II),NR^(I)SO₂R^(I), NR^(I)SO₂NR^(I)R^(II), OSO₂NR^(I)R^(II), SO_(p)R^(V),C₁₋₈ haloalkyl, C₃₋₁₃ carbocyclyl, heterocyclyl, carbocyclylalkyl, orheterocyclylalkyl, wherein each of said carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocylcylalkyl groups is optionally substitutedby one or more C₁₋₈ alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester,carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl orarylsufonyl;

R_(b) and R_(c) are each, independently, H, T, C₁₋₆alkylene-T,C₂₋₈alkenylene-T, C₂₋₆alkynylene-T, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, C(O)(CR_(b)′R_(c)′)_(r)-T,S(O)_(p)(CR_(b)′R_(c)′)_(r)-T, (CR_(c)′R_(b)′)—O—(CR_(c)′R_(b)′)_(r)-T,C(NR_(a)′R_(a)′)(═N—CN) or C(NR_(a)′R_(a)′)(═CHNO₂);

R_(d) and R_(f) are each, independently, H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, T, C₁₋₆alkylene-T, C₂₋₈alkenylene-T, C₂₋₆alkynylene-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-T,S(O)_(p)(CR_(b)′R_(c)′)_(r)-T or(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, OH, Cl, F, Br, I, CN, NO₂,NR^(I)R^(II), COR^(III), COOR^(II), OR^(IV), CONR^(I)R^(II), R^(I)NCONR^(I)R^(II), OCONR^(I)R^(II), R^(I)NCOR^(II), SO₂NR^(I)R^(II),NR^(I)SO₂R^(II), NR^(I)SO₂NR^(I)R^(II), OSO₂NR^(I)R^(II), —SO_(p)R^(V),C₁₋₈ haloalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl,heterocyclylalkyl, carbocyclyloxy or heterocarbocyclyloxy, wherein eachof said carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl,carbocyclyloxy or heterocarbocyclyloxy groups is optionally substitutedby one or more C₁₋₈ alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester,carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl orarylsufonyl;

T is H, C₁₋₁₀ alkyl substituted with 0 to 5 R_(b)′; C₂₋₁₀ alkenylsubstituted with 0 to 5 R_(b)′, C₂₋₁₀ alkynyl substituted with 0 to 5R_(b)′, C₃₋₁₃ carbocyclyl substituted with 0-3 R_(b)′, heterocyclylsubstituted with 0-5 R_(b)′;

R_(a)′, R_(b)′ and R_(c)′ are each, independently, H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OH, Cl, F, Br, I, CN, NO₂, NR^(I)R^(II),COR^(III), COOR^(IV), OR^(IV), CONR^(I)R^(II), R^(I) NCONR^(I)R^(II),OCONR^(I)R^(II), R^(I)NCOR^(II), SO₂NR^(I)R^(II), NR^(I)SO₂R^(I),NR^(I)SO₂NR^(I)R^(II), OSO₂NR^(I)R^(II), SO_(p)R^(V), C₁₋₈ haloalkyl,carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl,carbocyclyloxy or heterocarbocyclyloxy, wherein each of saidcarbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl,carbocyclyloxy or heterocarbocyclyloxy groups is optionally substitutedby one or more C₁₋₈ alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester,carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl orarylsufonyl;

R₁ is hydrogen, C₁₋₆ alkyl, SR₁₀, OR₁₀ or NR₁₁R₁₂;

R₂ is hydrogen, C₁₋₆ alkyl, SR₁₀, OR₁₀ or NR₁₁R₁₂;

R₃ is:

(i) C₁₋₁₀ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl;

(ii) C₃₋₁₃ carbocyclyl optionally substituted with one or moresubstituents selected from halogen, C₁₋₆ alkyl, SR₁₃, NR₁₁R₁₂, OR₁₃,heterocyclyl, aryl, ═S, ═O, CN, NO₂, NR_(β)R_(β)′, COR_(γ),R_(γ)NC(O)NR_(γ)R_(γ)′, OC(O)NR_(γ)R_(γ)′, C(O)OR_(γ), C(O)NR_(γ)R_(γ)′,or R_(γ)NC(O)O;

(iii) aryl optionally substituted with one or more substituents selectedfrom halogen, C₁₋₆ alkyl, SR₁₃, NR₁₁R₁₂, OR₁₃, heterocyclyl, aryl, ═S,═O, CN, NO₂, NR_(β)R_(β)′, COR_(γ), R_(γ)NC(O)NR_(γ)R_(γ)′,OC(O)NR_(γ)R_(γ)′, C(O)OR_(γ), C(O)NR_(γ)R_(γ)′, or R_(γ)NC(O)O;

(iv) heterocyclyl optionally substituted with one or more substituentsselected from halogen, C₁₋₆ alkyl, SR₁₃, NR₁₁R₁₂, OR₁₃, heterocyclyl,aryl, ═S, ═O, CN, NO₂, NR_(β)R_(β)′, COR_(γ), R_(γ)NC(O)NR_(γ)R_(γ)′,OC(O)NR_(γ)R_(γ)′, C(O)OR_(γ), C(O)NR_(γ)R_(γ)′, and R_(γ)NC(O)O;

(v) NR₁₄(CH₂)_(l)NR₁₄R₁₅; or

(vi) NR₁₆R₁₇;

R₄ and R₅ are each, independently, H, halogen, T, C₁₋₆alkylene-T,C₂₋₆alkynylene-T, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T,CO(CR_(b)′R_(c)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-T,S(O)_(p)(CR_(b)′R_(c)′)_(r)-T,(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, NR₁₁R₁₂, SR₁₈ or OR₁₈;

R₄′ is H, halogen, T, C₁₋₆alkylene-T, C₂₋₆alkynylene-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, CO(CR_(b)′R_(c))_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, S(O)_(p)(CR_(b)′R_(c)′)_(r)-T, or(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, NR₁₁R₁₂, SR₁₈, or OR₁₈;

R₅′ is H, halogen, T, C₁₋₆alkylene-T, C₂₋₆alkynylene-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, CO(CR_(b)′R_(c)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, S(O)_(p)(CR_(b)′R_(c)′)_(r)-T, or(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, NR₁₁R₁₂, SR₁₈, or OR₁₈;

or R₄′ and R₅′ together with the atoms to which they are attached form aring selected from C₃₋₁₃ carbocyclyl and 3-14 membered heterocyclyl;

W is oxygen or sulfur;

R₆ and R₇ are each, independently, hydrogen, C₁₋₆ alkyl, C₂₋₈ alkenyl orC₂₋₈ alkynyl;

R₈ is H, C₁₋₁₀ alkylene-T, C₂₋₁₀ alkenylene-T, and C₂₋₁₀ alkynylene-T,

(CR_(b)′R_(c))_(r)O(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)NR_(a)′ (CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)C(O)(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)C(O)O(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)OC(O)(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)C(O)NR_(a)′(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)NR_(a)′ C(O)(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)OC(O)O(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)OC(O)NR_(a)′(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)NR_(a)′ C(O)O(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)NR_(a)′ C(O)NR_(a)′ (CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)S(O)_(p)(CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)SO₂NR_(a)′ (CR_(b)′R_(c)′)_(r)-T,

(CR_(b)′R_(c))_(r)NR_(a)′ SO₂(CR_(b)′R_(c)′)_(r)-T, or

(CR_(b)′R_(c))_(r)SO₂NR_(a)′ SO₂(CR_(b)′R_(c)′)_(r)-T;

R₁₀ is H or C₁-C₆ alkyl;

R₁₁ and R₁₂ are each, independently, hydrogen or C₁-C₈ alkyl, or R₁₁ andR₁₂ together with the N atom to which they are attached form a 3-14member heterocyclic ring;

R₁₃ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃₋₁₃ carbocyclyl,carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, each of which isoptionally substituted by one or more halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, OH, COOH, amino, alkylamino,or dialkylamino;

R₁₄ and R₁₅ are each, independently, hydrogen, C₁₋₁₀ alkyl, C₃₋₁₃carbocyclyl substituted with one or more heterocyclyl, or R₁₄ and R₁₅together with the N atom to which they are attached form a 3-14 memberedheterocyclic system;

R₁₆ and R₁₇ are each, independently, hydrogen, C₁-C₁₀ alkyl, C₃-C₁₃carbocyclyl, aryl, C₃-C₁₃ carbocyclylalkyl or arylalkyl, wherein saidC₁-C₁₀ alkyl, C₃-C₁₃ carbocyclyl, aryl, C₃₋₁₃ carbocyclylalkyl orarylalkyl are each optionally substituted with one or more halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, OR₁₇′, SR₁₇′, COOR₁₇′, amino, alkylamino,dialkylamino or heterocyclyl;

or R₁₆ and R₁₇ together with the N atom to which they are attached forma 3-14 membered heterocycle substituted with 0-5 R_(α) or aresubstituted by one or more heterocyclyl, heterocyclylalkyl, C₃-C₁₃carbocyclyl or carbocyclylalkyl, wherein said heterocyclyl,heterocyclylalkyl, C₃-C₁₃ carbocyclyl or carbocyclylalkyl are eachoptionally substituted by one or more R_(α);

R₁₇′ is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₁₃ carbocyclyl,carbocyclylalkyl, heterocyclyl or heterocyclylalkyl, wherein said C₃₋₁₃carbocyclyl, carbocyclylalkyl, heterocyclyl or heterocyclylalkyl areeach optionally substituted by halo or C₁₋₄ alkyl;

R₁₈ is C₁₋₆ alkyl;

R_(α) is halogen, C₁₋₆ alkyl, C₂₋₈ alkyloxyalkyl, C₁₋₆ haloalkyl, SR₁₃,NR₁₁R₁₂, OH, OR₁₃, C₃₋₁₃ carbocyclyl, heterocyclyl, aryl, ═S, ═O, CN,NO₂, NR_(β)R_(β)′, COR_(γ), NR_(β)C(O)NR_(β)R_(β)′, OC(O)NR_(β)R_(β)′,C(O)NR_(β)R_(β)′, C(O)OR_(γ), NR_(β)C(O)OR_(γ) or NR_(β)C(O)R_(γ), ortwo R_(α) together with a carbon atom to which they are both attachedform a C₃₋₁₃ carbocycle;

R_(β), R_(β)′, R_(γ), and R_(γ)′ are each, independently, H, C₁₋₄ alkyl,phenyl or benzyl;

R^(I) and R^(II) are each, independently, H, C₁₋₆ alkyl or C₃₋₁₃carbocyclyl;

R^(III) and R^(II) are each, independently, H, C₁₋₆ alkyl, haloalkyl,carbocyclyl, heterocyclyl, carbocyclylalkyl or heterocyclylalkyl,wherein said carbocyclyl, heterocyclyl, carbocyclylalkyl orheterocyclylalkyl are each optionally substituted by one or more halo,C₁₋₄ alkyl or C₁₋₄ alkoxy;

R^(V) is C₁₋₆ alkyl, haloalkyl, carbocyclyl or heterocyclyl;

j=1, 2, 3 or 4;

i=0, 1 or 2;

l=2, 3, 4, 5, 6, 7 or 8;

n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

m=0, 1 or 2;

p=1 or 2; and

r=0, 1, 2, 3, 4 or 5.

The spiro ring is preferably a stable chemical entity.

In some embodiments, NR₈ and NR_(b) have no N—N or N—O bonds.

In some embodiments, A is CWNHOH, CWNHOR₅, N(OH)CHO or N(OH)CWR₆.

In some embodiments, A is CWNHOH or CWNHOR₅.

In some embodiments, A is C(O)NHOH.

In some embodiments, B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), O(C═W)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n).

In some embodiments, B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), O(C═W)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n).

In some embodiments, B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), O(C═W)NR₈, C(O)NR₈(CR_(d)R_(f))_(n) orC(O)(CR_(d)R_(f))_(n).

In some embodiments, B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NRor NR₈(CR_(d)R_(f))_(n).

In some embodiments, B is (CH₂)_(n).

In some embodiments, B is CH₂.

In some embodiments, G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), O(C═W)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f)).

In some embodiments, G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), O(C═W)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n).

In some embodiments, G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), O(C═W)NR₈, C(O)NR₈(CR_(d)R_(f)), orC(O)(CR_(d)R_(f))_(n).

In some embodiments, G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n).

In some embodiments, G is (CH₂)_(n).

In some embodiments, G is CH₂.

In some embodiments, B and G are both CH₂.

In some embodiments, D is oxygen.

In some embodiments, X is (CH₂)_(j), C₁₋₁₀ alkylene substituted with 0to 3 R_(a), NR_(b), S(O)_(n), C═O, NR_(b)C(O), NR_(b)C(O)O,NR_(b)C(O)NR_(b), C(O)O, OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m),NR_(b)S(O)NR_(b), or (CR_(d)R_(f))_(j)NR_(b), NR_(b)(CR_(d)R_(f))_(j).

In some embodiments, X is (CH₂)_(j), NR_(b), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j).

In some embodiments, X is (CH₂)_(j), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j).

In some embodiments, X is CH₂NR_(b), CH₂CH₂ or NR_(b)CH₂CH₂.

In some embodiments, X is CH₂NR_(b).

In some embodiments, Y is absent, (CH₂)_(j), C₁₋₁₀ alkylene substitutedwith 0 to 3 R_(a), NR_(b), S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O,NR_(b)C(O)NR_(b), C(O)O, OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m),NR_(b)S(O)NR_(b), or (CR_(d)R_(f))_(j)NR_(b), NR_(b)(CR_(d)R_(f))_(j).

In some embodiments, Y is absent, (CH₂)_(j), NR_(b),(CR_(d)R_(f))_(j)NR_(b) or NR_(b)(CR_(d)R_(f))_(j).

In some embodiments, Y is absent, (CH₂)_(j), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j).

In some embodiments, Y is absent, CH₂, CH₂NR_(b), CH₂CH₂ orNR_(b)CH₂CH₂.

In some embodiments, Y is absent or CH₂.

In some embodiments, Y is CH₂.

In some embodiments, R₁ is H.

In some embodiments, R₂ is H.

In some embodiments, R₄ is H.

In some embodiments, R₄′ is H.

In some embodiments, R₅′ is H.

In some embodiments, R₃ is NR₁₆R₁₇.

In some embodiments, M is CO.

In some embodiments, U is absent.

In some embodiments, V is heterocyclyl substituted with 0-5 R_(e).

In some embodiments, V is azetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,piperindin-1yl, piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl,pyridin-1-yl, 3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl,1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl,3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl,1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl,pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl,1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl,1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl,3,3a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, or2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl.

In some embodiments, U′ is absent, O or C₁₋₁₀ alkylene substituted with0 to 5 R_(a).

In some embodiments, U′ is absent.

In some embodiments, V′ is C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e)or heterocyclyl substituted with 0-5 R_(e).

In some embodiments, V′ is C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e).

In some embodiments, V′ is phenyl substituted with 0-5 R_(e).

In some embodiments, V′ is phenyl substituted with 0-5 T,C₁₋₈alkylene-T, (CR_(b)′R_(c)′)_(r)—O—(CR_(b)′R_(c)′)_(r)-T, OH, Cl, F,Br, I, CN, NO₂, OR^(V), CONR^(I)R^(II) or NR^(I)COR^(II).

In some embodiments, V′ is phenyl.

In some embodiments, V′ is heterocyclyl substituted with 0-5 R_(e).

In some embodiments, V′ is thiazolyl, benzothiazolyl, thienyl,quinolinyl, pyridinyl, pyarazinyl, benzimidazolyl, indazolyl,3,6-dihydropyridinyl, piperidinyl or 2,3-dihydro-benzofuran-5-yl.

In some embodiments, U′ is O or C₁₋₁₀ alkylene and V′ is C₃₋₁₃carbocyclyl substituted with 0-5 R_(e) or heterocyclyl substituted with0-5 R_(e).

In some embodiments, M is CO, U is absent, V is heterocyclyl substitutedwith 0-5 R_(e), U′ is absent, and V′ is C₃₋₁₃ carbocyclyl substitutedwith 0-5 R_(e) or heterocyclyl substituted with 0-5 R_(e).

In some embodiments, M is CO, U is absent, V is absent, U′ is absent andV′ is NR_(b)R_(c).

In some embodiments, R_(b) and R_(c) are each, independently, H,C₁₋₆alkylene-T, C(O)NR_(a)′ (CR_(c)′R_(b)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, C(O)(CR_(b)′R_(c)′)_(r)-T,S(O)_(p)(CR_(b)′R_(c)′)_(r)-T,(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO₂).

In some embodiments, R_(b) and R_(c) are each, independently, H, C₁₋₄alkyl, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-T,S(O)_(p)(CR_(b)′R_(c)′)_(r)-T,(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO2).

In some embodiments, R_(b) is H, C₁₋₄ alkyl, C(O)(CR_(b)′R_(c)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T, S(O)_(p)(CR_(b)′R_(c)′)_(r)-T or(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T.

In some embodiments, R_(b) is H.

In some embodiments, R_(b) is C₁₋₄ alkyl.

In some embodiments, R_(b) is C(O)(CR_(b)′R_(c)′)_(r)-T.

In some embodiments, R_(b) is C(O)O(CR_(b)′R_(c)′)_(r)-T.

In some embodiments, R_(b) is S(O)_(p)(CR_(b)′R_(c)′)_(r)-T.

In some embodiments, R_(b) is(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T.

In some embodiments, R_(c) is H or C₁₋₄ alkyl.

In some embodiments, R_(e) is H, T, C₁₋₈alkylene-T,C(O)NR_(a)′(CR_(b)′R_(c)′)_(r)-T,(CR_(b)′R_(c)′)_(r)—O—(CR_(b)′R_(c)′)_(r)-T, OH, Cl, F, Br, I, CN, NO₂,OR^(V), NR^(I)R^(II), CONR^(I)R^(II), NR^(I)COR^(II), SO₂NR^(I)R^(II)C₁₋₈ haloalkyl, C₃₋₁₃ carbocyclyl, heterocyclyl, carbocyclylalkyl, orheterocyclylalkyl, wherein each of said carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocylcylalkyl groups is optionally substitutedby one or more C₁₋₈ alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano,nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester,carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl orarylsufonyl.

In some embodiments, wherein R_(e) is H, C₁₋₆ alkyl, OH, Cl, F, Br, I,CN, NO₂, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, benzyloxy,amino, (C₁₋₄ alkyl)amino, (C₂₋₈)dialkylamino, C(O)O(C₁₋₄ alkyl), CONH₂,CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, C₁₋₆ haloalkyl, phenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, or phenethyl.

In some embodiments, R₄′ is C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T or S(O)_(p)(CR_(b)′R_(c)′)_(r)-T.

In some embodiments, R₅′ is C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T,C(O)O(CR_(b)′R_(c)′)_(r)-T or S(O)_(p)(CR_(b)′R_(c)′)_(r)-T.

In some embodiments, r is 0, 1 or 2.

In some embodiments, n is 0, 1 or 2.

In some embodiments, j is 1 or 2.

In some embodiments, said compound has Formula II.

In some embodiments, the compound has Formula II wherein:

A is CWNHOH,

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n);

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n);

X is absent, (CH₂)_(j), C₁₋₁₀ alkylene substituted with 0 to 3 R_(a), O,NR_(b), S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O,OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m), NR_(b)S(O)NR_(b),(CR_(d)R_(f))_(j)NR_(b) or NR_(b)(CR_(d)R_(f))_(j);

Y is absent, (CH₂)_(j), C₁₋₁₀ alkylene substituted with 0 to 3 R_(a), O,NR_(b), S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O,OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m), NR_(b)S(O)NR_(b),(CR_(d)R_(f))_(j)NR_(b) or NR_(b)(CR_(d)R_(f))_(j);

M is CO;

U is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), O, NR_(b),S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O, OC(O),S(O)_(m)NR_(b), NR_(b)S(O)_(m) or NR_(b)S(O)NR_(b);

V is absent, C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e) orheterocyclyl substituted with 0-5R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), O,NR_(b)S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O,OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m), or NR_(b)S(O)NR_(b);

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R₁ is hydrogen;

R₂ is hydrogen;

R₃ is NR₁₆R₁₇;

R₄′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;

R₅′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T; and

W is oxygen.

In some embodiments, the compound has Formula II wherein:

A is C(O)NHOH;

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n);

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f)), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f)) or C(O)(CR_(d)R_(f));

X is absent, (CH₂)_(j), NR_(b), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j);

Y is absent, (CH₂)_(j), NR_(b), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j);

M is CO;

U is absent;

V is absent, C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e) orheterocyclyl substituted with 0-5R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), O,NR_(b)S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O,OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m), or NR_(b)S(O)NR_(b);

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R_(b) and R_(c) are each, independently, H, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;

R_(d) and R_(f) are each, independently, H or C₁₋₆ alkyl;

R₁ is hydrogen;

R₂ is hydrogen;

R₃ is NR₁₆R₁₇;

R₄′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T; and

R₅′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;

In some embodiments, the compound has Formula II wherein:

A is C(O)NHOH;

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f)) or C(O)(CR_(d)R_(f));

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r),(CR_(d)R_(f))_(n)S(CR_(d)R_(f))_(r), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f)) or C(O)(CR_(d)R_(f));

X is absent, (CH₂)_(j), NR_(b), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j);

Y is absent, (CH₂)_(j), NR_(b), (CR_(d)R_(f))_(j)NR_(b) orNR_(b)(CR_(d)R_(f))_(j);

M is CO;

U is absent;

V is absent, C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e) orheterocyclyl substituted with 0-5R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), O,NR_(b)S(O)_(m), C═O, NR_(b)C(O), NR_(b)C(O)O, NR_(b)C(O)NR_(b), C(O)O,OC(O), S(O)_(m)NR_(b), NR_(b)S(O)_(m), or NR_(b)S(O)NR_(b);

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R_(b) and R_(c) are each, independently, H, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T; C(O)(CR_(b)′R_(c)′)_(r)-T,(CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO₂);

R_(d) and R_(f) are each, independently, H or C₁₋₆ alkyl;

R_(a)′ is H or C₁₋₆ alkyl;

R_(b)′ and R_(e)′ are each, independently, H, C₁₋₆ alkyl, OH, Cl, F, Br,I, CN, NO₂, NR^(I)R^(II), OR^(V) or haloalkyl;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;

R₅′ is H, C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(O)O(CR_(b)′R_(c)′)_(r)-Tor S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;

j=1 or 2;

l=2, 3 or 4;

n=0, 1, 2, 3 or 4; and

r=0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))NR₈, NR₈(CR_(d)R_(f))_(n),(CR_(d)R_(f))_(n)O(CR_(d)R_(f))_(r), (CR_(d)R_(f))_(n)S(CR_(d)R_(f)),OC(O)NR₈, O, NR₈, S(O)_(m), S, C(O)NR₈(CR_(d)R_(f))_(n) orC(O)(CR_(d)R_(f))_(n);

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈,NR₈(CR_(d)R_(f))_(n), (CR_(d)R_(f))_(n)O(CR_(d)R_(f)),(CR_(d)R_(f))_(n)S(CR_(d)R_(f)), OC(O)NR₈, O, NR₈, S(O)_(m), S,C(O)NR₈(CR_(d)R_(f))_(n) or C(O)(CR_(d)R_(f))_(n);

X is absent, (CH₂)_(j), CH₂NR_(b) or NR_(b)CH₂CH₂;

Y is absent, (CH₂)_(j), CH₂NR_(b) or NR_(b)CH₂CH₂;

M is CO;

U is absent;

V is heterocyclyl substituted with 0-5 R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), or O;

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;C(O)(CR_(b)′R_(c)′)_(r)-T, (CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO₂);

R_(c) is H, T, C₁₋₆alkylene-T, C₂₋₈alkenylene-T or C₂₋₆alkynylene-T;

R_(d) and R_(f) are each, independently, H or C₁₋₆ alkyl;

R_(a)′ is H or C₁₋₆ alkyl;

R_(b)′ and R_(e)′ are each, independently, H, C₁₋₆ alkyl, OH, Cl, F, Br,I, CN, NO₂, NR^(I)R^(II), OR^(IV) or haloalkyl;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j=1 or 2;

l=2, 3 or 4;

n=0, 1, 2, 3 or 4; and

r=0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈ or NR₈(CR_(d)R_(f));

G is (CH₂)_(n), (CH₂)_(n)C═W, (CR_(d)R_(f))_(n)NR₈ orNR₈(CR_(d)R_(f))_(n);

X is absent, (CH₂)₁, CH₂NR_(b) or NR_(b)CH₂CH₂;

Y is absent, (CH₂)_(j), CH₂NR_(b) or NR_(b)CH₂CH₂;

M is CO;

U is absent;

V is heterocyclyl substituted with 0-5 R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), or O;

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;C(O)(CR_(b)′R_(c)′)_(r)-T, (CR_(c)′R_(b)′)_(Y)—O—(CR_(c)′R_(b)′)_(r)-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO₂);

R_(c) is H, T, C₁₋₆alkylene-T, C₂₋₈alkenylene-T or C₂₋₆alkynylene-T;

R_(d) and R_(f) are each, independently, H or C₁₋₆ alkyl;

R_(a)′ is H or C₁₋₆ alkyl;

R_(b)′ and R_(e)′ are each, independently, H, C₁₋₆ alkyl, OH, Cl, F, Br,I, CN, NO₂, NR^(I)R^(II), OR^(V) or haloalkyl;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j=1 or 2;

l=2, 3 or 4;

n=0, 1, 2, 3 or 4; and

r=0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is (CH₂)_(n);

G is (CH₂)_(n);

X is absent, (CH₂)_(j), CH₂NR_(b) or NR_(b)CH₂CH₂;

Y is absent, (CH₂)_(j), CH₂NR_(b) or NR_(b)CH₂CH₂;

M is CO;

U is absent;

V is heterocyclyl substituted with 0-5 R_(e);

U′ is absent, C₁₋₁₀ alkylene substituted with 0 to 5 R_(a), or O;

V′ is H, C₁₋₈ alkyl, NR_(b)R_(c), C₃₋₁₃ carbocyclyl substituted with 0-5R_(e) or heterocyclyl substituted with 0-5 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or S(O)_(p)(CR_(b)′R_(c)′)_(r)-T;C(O)(CR_(b)′R_(c)′)_(r)-T, (CR_(c)′R_(b)′)_(r)—O—(CR_(c)′R_(b)′)_(r)-T,C(O)NR_(a)′(CR_(c)′R_(b)′)_(r)-T, C(NR_(a)′R_(a)′)(═N—CN) orC(NR_(a)′R_(a)′)(═CHNO₂);

R_(c) is H, T, C₁₋₆alkylene-T, C₂₋₈alkenylene-T or C₂₋₆alkynylene-T;

R_(a)′ is H or C₁₋₆ alkyl;

R_(b)′ and R_(e)′ are each, independently, H, C₁₋₆ alkyl, OH, Cl, F, Br,I, CN, NO₂, NR^(I)R^(II), ORw or haloalkyl;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j=1 or 2;

l=2, 3 or 4;

n=0, 1, 2, 3 or 4; and

r=0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is CH₂;

G is CH₂;

X is CH₂NR_(b);

Y is (CH₂)_(j);

M is CO;

U is absent;

V is azetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl,piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl, pyridin-1-yl,3,6-dihydropyridin-1l-yl, 2,3-dihydroindol-1-yl,1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl,3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl,1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl,pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl,1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl,1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl,3,3a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, or2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl;

U′ is absent;

V′ is C₃₋₁₃ carbocyclyl substituted with 0-5 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or C(O)(CR_(b)′R_(c)′)_(r)-T;

R_(a)′ is H or C₁₋₆ alkyl;

R_(b)′ and R_(e)′ are both H;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j=1 or 2; and

r=0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is CH₂;

G is CH₂;

X is CH₂NR_(b);

Y is (CH₂)_(j);

M is CO;

U is absent;

V is piperindin-1yl, piperazin-1-yl, pyrrolidin-1-yl, pyridin-1-yl or3,6-dihydropyridin-1-yl;

U′ is absent;

V′ is C₃₋₁₃ aryl substituted with 0-5 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or C(O)(CR_(b)′R_(c)′)_(r)-T;R_(b)′ and R_(e)′ are both H;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j is 1 or 2; and

r is 0, 1 or 2.

In some embodiments, the compound has Formula II wherein:

A is CONHOH;

B is CH₂;

G is CH₂;

X is CH₂NR_(b);

Y is (CH₂)_(j);

M is CO;

U is absent;

V is piperindin-1yl, piperazin-1-yl, pyrrolidin-1-yl, pyridin-1-yl or3,6-dihydropyridin-1-yl;

U′ is absent;

V′ is phenyl substituted with 0-3 R_(e);

R_(b) is H, C(O)O(CR_(b)′R_(c)′)_(r)-T or C(O)(CR_(b)′R_(c)′)_(r)-T;

R_(b)′ and R_(e)′ are both H;

R₁ is hydrogen;

R₂ is hydrogen;

R₄′ is H;

R₅′ is H;

j is 1 or 2; and

r is 0, 1 or 2.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges.

For example, the term “C₁₋₆ alkyl” is specifically intended toindividually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, andC₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R₁ groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of thehydrogen atoms are replaced with halogen atoms can be referred to as“perhaloalkyl.”

As used herein, “alkylene” or “alkylenyl” refers to a bivalent alkylgroup. An example alkylene group is methylene or ethylene.

As used herein, “alkenylene” or “alkenylenyl” refers to a bivalentalkenyl group.

As used herein, “carbocyclyl” groups are saturated (i.e., containing nodouble or triple bonds) or unsaturated (i.e., containing one or moredouble or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groupscan be mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) orspirocyclic. Example carbocyclyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,1,3-cyclopentadienyl, cyclohexenyl, norbomyl, norpinyl, norcamyl,adamantyl, phenyl, and the like. Carbocyclyl groups can be aromatic(e.g., “aryl”) or non-aromatic (e.g., “cycloalkyl”). In someembodiments, carbocyclyl groups can have from about 3 to about 30 carbonatoms, about 3 to about 20, about 3 to about 10, or about 3 to about 7carbon atoms.

As used herein, “aryl” refers to an aromatic carbocyclyl group includingmonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatichydrocarbons such as, for example, phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to about 20 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclyl groupsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include bi- or polycyclic (e.g., having 2, 3 or 4 fused rings) ringsystems as well as spiro ring systems. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbomyl, norpinyl, norcamyl, adamantyl, and the like. Also included inthe definition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of pentane, pentene, hexane, and thelike.

As used herein, “heterocyclyl” or “heterocycle” refers to a saturated orunsaturated carbocyclyl group wherein one or more of the ring-formingcarbon atoms of the carbocyclyl group is replaced by a heteroatom suchas O, S, or N. Heterocyclyl groups can be aromatic (e.g., “heteroaryl”)or non-aromatic (e.g., “heterocycloalkyl”). Heterocyclyl groups can alsocorrespond to hydrogenated and partially hydrogenated heteroaryl groups.Heterocyclyl groups can be characterized as having 3-14 ring-formingatoms. In some embodiments, heterocyclyl groups can contain, in additionto at least one heteroatom, from about 1 to about 20, about 2 to about10, or about 2 to about 7 carbon atoms and can be attached through acarbon atom or heteroatom. In further embodiments, the heteroatom can beoxidized (e.g., have an oxo or sulfindo substituent) or a nitrogen atomcan be quatemized. Examples of heterocyclyl groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well asany of the groups listed below for “heteroaryl” and “heterocycloalkyl.”Further example heterocycles include pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,3,6-dihydropyridyl, 1,2,3,6-tetrahydropyridyl,1,2,5,6-tetrahydropyridyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thia-diazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzo-thiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, deca-hydroquinolinyl, 2H,6H-1,5,2dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl and isoxazolyl. Further examples of heterocycles includeazetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl,piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl, pyridin-1-yl,3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl,1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl,3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl,1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl,pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl,1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl,1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl,3,3a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, and2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl. Also included are fusedring and spiro compounds containing, for example, the aboveheterocycles.

As used herein, “heteroaryl” groups are aromatic heterocyclyl groups andinclude monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings)aromatic hydrocarbons that have at least one heteroatom ring member suchas sulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, and the like. In some embodiments, the heteroaryl group hasfrom 1 to about 20 carbon atoms, and in further embodiments from about 3to about 20 carbon atoms. In some embodiments, the heteroaryl groupcontains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. Insome embodiments, the heteroaryl group has 1 to about 4, 1 to about 3,or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclylgroups including cyclized alkyl, alkenyl, and alkynyl groups where oneor more of the ring-forming carbon atoms is replaced by a heteroatomsuch as an O, N, or S atom. Example heterocycloalkyl” groups includemorpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole,benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, and the like. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the nonaromatic heterocyclicring, for example phthalimidyl, naphthalimidyl, and benzo derivatives ofheterocycles such as indolene and isoindolene groups. In someembodiments, the heterocycloalkyl group has from 1 to about 20 carbonatoms, and in further embodiments from about 3 to about 20 carbon atoms.In some embodiments, the heterocycloalkyl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2heteroatoms. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 triple bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “aryloxy” refers to an —O-aryl group. An example aryloxygroup is phenoxy.

As used here, “haloalkoxy” refers to an —O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “carbocyclylalkyl” refers to an alkyl moiety substitutedby a carbocyclyl group. Example carbocyclylalkyl groups include“aralkyl” (alkyl substituted by aryl (“arylalkyl”)) and“cycloalkylalkyl” (alkyl substituted by cycloalkyl). In someembodiments, carbocyclylalkyl groups have from 4 to 24 carbon atoms.

As used herein, “heterocyclylalkyl” refers to an alkyl moietysubstituted by a heterocarbocyclyl group. Example heterocarbocyclylalkylgroups include “heteroarylalkyl” (alkyl substituted by heteroaryl) and“heterocycloalkylalkyl” (alkyl substituted by heterocycloalkyl). In someembodiments, heterocyclylalkyl groups have from 3 to 24 carbon atoms inaddition to at least one ring-forming heteroatom.

As used herein, “amino” refers to an NH₂ group. “Alkylamino” refers toan amino group substituted by an alkyl group and “dialkylamino” refersto an amino group substituted by two alkyl groups.

As used herein, “aminocarbonyl” refers to CONH₂.

As used herein, “alkylaminocarbonyl” refers to CONH(alkyl).

As used herein, “alkylaminocarbonyl” refers to CON(alkyl)₂.

As used herein, “carboxy” or “carboxyl” refers to COOH.

As used herein, “carboxy alkyl ester” refers to COO-alkyl.

As used herein, “carboxy aryl ester” refers to COO-aryl.

As used herein, “hydroxy” refers to OH.

As used herein, “mercapto” refers to SH.

As used herein, “sulfinyl” refers to SO.

As used herein, “sulfonyl” refers to SO₂.

As used herein, “aminosulfonyl” refers to SO₂NH₂.

As used herein, “alkylaminosulfonyl” refers to SO₂NH(alkyl).

As used herein, “dialkylaminosulfonyl” refers to SO₂N(alkyl)₂.

As used herein, “arylsulfonyl” refers to SO₂-aryl.

As used herein, “arylsulfinyl” refers to SO-aryl.

As used herein, “alkylsulfonyl” refers to SO₂-alkyl.

As used herein, “alkylsulfinyl” refers to SO-alkyl.

As used herein, “combinations thereof” is meant to refer toconcatenation of two or more moieties recited for a given variable. Forexample, “CH₂, NH, CO, and combinations thereof” would include CH₂NH,CH₂CO, CONH, CH₂NHCO, and other stable combinations.

Unless otherwise indicated, the compounds provided in the above formulaare meant to include pharmaceutically acceptable salts, prodrugs,enantiomers, diastereomers, racemic mixtures, crystalline forms,non-crystalline forms, amorphous forms, hydrates and solvates thereof.

The term “pharmaceutically acceptable salt” is meant to refer to saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, phosphoric, partially neutralizedphosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic,or phosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like. Certain specificcompounds of the present invention may contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds of the present invention may beregenerated by contacting the salt with a base or acid and isolating theparent compound in the conventional manner. The parent form of thecompound differs from the various salt forms in certain physicalproperties, such as solubility in polar solvents, but otherwise thesalts are equivalent to the parent form of the compound for the purposesof the present invention.

As noted above, some of the compounds of the present invention possesschiral or asymmetric carbon atoms (optical centers) or double bonds; theracemates, diastereomers, geometric isomers and individual opticalisomers are all intended to be encompassed within the scope of thepresent invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Some of the compounds of the invention can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

In addition to salt forms, the present invention provides compounds maybe in a prodrug form. Prodrugs of the compounds described herein arethose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex-vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

In some embodiments, the present invention provides a compound selectedfrom:

-   N-hydroxy-5-methyl-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-chlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-quinolin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2,3-dichlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-quinolin-4-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-methylquinolin-4-yl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-phenylethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-pyridin-4-ylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(4-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-phenoxypiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-(4,7-dihydrothieno[2,3-c]pyridin-6(5H)-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(3-benzylpyrrolidin-1-yl)carbonyl]-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-pyridin-4-ylethyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-(1,4′-bipiperidin-1′-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(pyridin-2-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(pyridin-4-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(pyri    din-3-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-(1,3,4,9-tetrahydro-2H-3-carbolin-2-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(9-methyl-1,3,4,9-tetrahydro-2H-3-carbolin-2-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-fluorophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-chlorophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-nitrophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-phenyl-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N(7)-hydroxy-N(6),5-dimethyl-N(6)-(3-phenylpropyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-hydroxy-N(6)-isobutyl-5-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N-hydroxy-5-methyl-6-{[4-(2-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N(7)-hydroxy-N(6)-isobutyl-N(6),5-dimethyl-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-hydroxy-5-methyl-N(6)-(2-phenoxyethyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-hydroxy-N(6)-[2-(4-methoxyphenyl)ethyl]-5-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-hydroxy-5-methyl-N(6)-(4-phenylbutyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-hydroxy-5-methyl-N(6)-[3-(2-oxopyrrolidin-1-yl)propyl]-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N-hydroxy-5-methyl-6-[(10a)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-ylcarbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   (5,6-trans)-N-hydroxy-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamide;-   (5,6-trans)-N-hydroxy-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide;-   (5,6-trans)-N-hydroxy-5-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]spiro[2.5]octane-6-carboxamide;-   (5,6-trans)-N-hydroxy-5-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamide;-   (5,6-trans)-N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide;-   N-hydroxy-6-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl 7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Benzyl 7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-Hydroxy-5-(methylsulfonyl)-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[3-(2-phenylethyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3-(aminocarbonyl)phenyl]-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(2-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(2-methyl-3-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-(3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N(7)-hydroxy-N(6)-(4-methoxyphenyl)-N(6)-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N-hydroxy-6-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3-chlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(4-phenyl-1,4-diazepan-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-methyl-4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-phenylpyrrolidin-1-yl)carbonyl]spiro[2.5]octane-5-carboxamide;-   N-hydroxy-6-[(4-isobutyrylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N(7)-Hydroxy-5-methyl-N(6)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   N(7)-Hydroxy-N(6)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.5]octane-6,7-dicarboxamide;-   6-{[4-(4-cyanophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-6-carboxamide;-   N-hydroxy-6-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-({4-[3-(methoxymethyl)phenyl]piperidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    3-[1-({7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]benzoate;-   6-[(3-Cyclohexylpyrrolidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-propylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-ethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[4-(4-ethylphenyl)piperidin-1l-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[4-(3-isopropoxyphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[4-(3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[4-(3-methylphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(3-Benzylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(5-methoxy-2,3-dihydro-1H-indol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-({5-[(2-methylquinolin-4-yl)methoxy]-2,3-dihydro-1H-indol-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-({5-[(2-methylquinolin-4-yl)methoxy]-2,3-dihydro-1H-indol-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[5-(benzyloxy)-2,3-dihydro-1H-indol-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-(1,3-dihydro-1′H-spiro[indene-2,4′-piperidin]-1′-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-isopropoxyphenyl)piperidin-1l-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    4-[1-({7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methylbenzoate;-   N-hydroxy-6-{[4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-ethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    4-[1-({7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]-3-methylbenzoate;-   6-{[4-(2,3-dihydro-1-benzofuran-5-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-Hydroxy-6-{[(3    S)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-({3-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(3-chlorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(3-fluorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(4-fluorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(4-chlorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-({3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(4-methoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(4-phenoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-methoxyphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-cyano-3-methylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[3-(3-methoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-pyridin-4-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-trifluoromethoxyphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[5-(methoxy methyl)-4-phenyl-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-(1,4,5,6-tetrahydrobenzo[f]isoquinolin-3(2H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(5-methoxy-2-methylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-methoxy-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(4-cyano-4-phenylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Ethyl 7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Propyl 7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Isopropyl    7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Isobutyl    7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate; and-   N-hydroxy-6-[(5-methyl-4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide.-   Compounds of the invention further include:-   6-(1,4,4a,5,6,10b-hexahydrobenzo[f]isoquinolin-3(2H)-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-fluorophenyl)-3-hydroxypiperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-(3,3a,8,8a-tetrahydroindeno[1,2-c]pyrrol-2(1H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-phenyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-tert-Butyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(4-methyl-4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(4-ethyl-1,3-thiazol-2-yl)piperidin-1l-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[(trans)-3-methyl-4-phenylpyrrolidin-1l-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   Tetrahydro-2H-pyran-4-yl-7-((hydroxyamino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate;-   Ethyl    7-((hydroxyamino)carbonyl))-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5-carboxylate;-   Methyl    7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-6-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(4-quinolin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    7-[(hydroxyamino)carbonyl]-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-6-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-pyridin-2-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-methyl-3-phenylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-phenylazetidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(3-methyl-3-phenylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-methyl-6-[(3-phenylazetidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-(1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindol-2-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(2-naphthyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(2-thienyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(3-thienyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(2-thienyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(2-thienyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(2-methylphenyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[3-(4-methylphenyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   5-acetyl-N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-thienyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-[(3-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(3-thienyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-dichlorophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3,5-bis(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-(methylsulfonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   5-formyl-N-hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-difluorophenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2,4,5-trimethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(4-biphenyl-3-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(4-dibenzo[b,d]furan-4-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2,5-dimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2,4,5-trimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    3-[1-({7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-methylbenzoate;-   6-[(5-phenyl-2,3,4,7-tetrahydro-1H-azepin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3-(dimethylamino)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    3-[1-({7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]-4-methylbenzoate;-   6-[(5-phenylazepan-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-({4-[3-(dimethylamino)phenyl]piperidin-1-yl}carbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(3,3-dimethyl-4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(3,3-dimethyl-4-phenylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-5-(methylsulfonyl)-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-5-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3-(benzyloxy)phenyl]-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3-ethylphenyl]-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-[3-(ethyloxy)phenyl]-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3-ethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3-cyclopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-methoxy-3,5-dimethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-dimethyl-4-methoxyphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-ethylphenyl)piperidin-1l-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3,5-dimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(1,3-benzothiazol-6-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-methyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-methyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-isopropylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-methyl-1H-indazol-5-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-methyl-1H-indazol-5-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[4-(1-ethyl-1H-indazol-5-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   Tetrahydro-2H-pyran-4-yl    6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Methyl    6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Methyl    6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   Tetrahydro-2H-pyran-4-yl    6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Tetrahydro-2H-pyran-4-yl    6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-6-[(3-methyl-4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[5-(aminocarbonyl)-4-phenyl-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyanophenyl)-5-methyl-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(4-cyanophenyl)-3-methylpiperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[5-methyl-4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   N-hydroxy-6-{[5-methyl-4-(3-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(4-dibenzo[b,d]furan-2-yl-3,6-dihydropyridin-1    (2H)-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-[(4-dibenzo[b,d]furan-2-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide;-   Isopropyl    7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   (3 S)-tetrahydrofuran-3-yl    7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Cyclohexyl    7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Tetrahydro-2H-pyran-4-yl    7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)    octane-5-carboxamide;-   N-hydroxy-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide;-   N-hydroxy-6-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide;-   N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide;-   (3 S)-tetrahydrofuran-3-yl    7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   (3R)-tetrahydrofuran-3-yl    7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   2-Methoxyethyl    7-((hydroxyamino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate;-   N-hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;-   Propyl    7-[(hydroxyamino)carbonyl)]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2,5]octane-5-carboxylate;-   Isopropyl    7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Methyl 6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   Methyl 6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1    (2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate;-   N-hydroxy-6-{[4-(4-isopropylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide;-   6-{[4-(3,5-difluorophenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide;    and-   6-{[4-(4,5-dimethyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide.-   In some embodiments, compounds of the invention include:-   5-Methyl-6-(4-m-tolyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-phenyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane    7-carboxylic acid hydroxyamide;-   5-Methyl-6-(4-o-tolyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Chloro-phenyl)-piperazine-1-carbonyl]-5-methyl-5-aza-spir[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(2-methyl-4-nitro-phenyl)-piperazine-1-carbonyl]-5-aza    spiro[2.5]octane-7-carboxylic acid hydroxyamide;-   5-Methyl-6-(4-phenyl-piperidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-Hydroxy-4-phenyl-piperidine-1-carbonyl)-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-quinolin-2-yl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2,3-Dichloro-phenyl)-piperazine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-quinolin-4-yl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(2-methyl-quinolin-4-yl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-phenethyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(4-nitro-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Methoxy-phenyl)-piperazine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-phenoxy-piperidine-1-carbonyl)-5-aza-spiro[2.5]-carboxylic    acid hydroxyamide;-   6-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4,7-Dihydro-5H-thieno[2,3-c]pyridine-6-carbonyl)-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Benzyl-pyrrolidine-1-carbonyl)-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-pyridin-2-yl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(2-pyridin-4-yl-ethyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-([1,4′]Bipiperidinyl-1′-carbonyl)-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-pyridin-2-ylmethyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-pyridin-4-ylmethyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-pyridin-3-ylmethyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(4-o-tolyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-m-Tolyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(1,3,4,9-Tetrahydro-b-carboline-2-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(9-Methyl-1,3,4,9-tetrahydro-b-carboline-2-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-Phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Methyl-4-nitro-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-[methyl-(3-phenyl-propyl)-amide;-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-(isobutyl-amide);-   5-Methyl-6-[4-(2-nitro-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7    carboxylic acid hydroxyamide;-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-(isobutylmethyl-amide);-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-[(2-phenoxy-ethyl)-amide];-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-{[2-(4-methoxy-phenyl)-ethyl]-amide};-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-[(4-phenylbutyl)-amide];-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-{[3-(2-oxo pyrrolidin-1-yl)-propyl]-amide};-   6-(3,4,10,10a-Tetrahydro-1H-pyrazino[1,2-a]indole-2-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-[4-(2-Methyl-4-nitro-phenyl)-piperazine-1-carbonyl]-spiro[2.5]octane-6-carboxylic    acid hydroxyamide;-   6-(4-m-Tolyl-piperazine-1-carbonyl)-spiro[2.5]octane-5-carboxylic    acid hydroxyamide;-   5-(4-Phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-spiro[2.5]octane-6-carboxylic    acid hydroxyamide;-   5-(4-m-Tolyl-piperazine-1-carbonyl)-spiro[2.5]octane-6-carboxylic    acid hydroxyamide;-   6-(4-Phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-spiro[2.5]octane-5-carboxylic    acid hydroxyamide;-   6-(3,4,10,10a-Tetrahydro-1H-pyrazino[1,2-a]indole-2-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(1,2,4,4a,5,6-Hexahydro-pyrazino[1,2-a]quinoline-3-carbonyl)-5-methyl-5    azaspiro[2.5]-octane-7-carboxylic acid hydroxyamide;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid methyl ester;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid benzyl ester;-   5-Methanesulfonyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(3-Methoxy-phenyl)-piperidine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-(3-phenethyl-pyrrolidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Methoxy-phenyl)-piperidine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Carbamoyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Fluoro-2-methyl-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Methyl-3-nitro-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3′,6′-Dihydro-2′H-[3,4′]bipyridinyl-1′-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-[(4-methoxy-phenyl)-methyl-amide];-   6-[4-(3-Methoxy-phenyl)-piperazine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Chloro-phenyl)-piperazine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-Phenyl-[1,4]diazepane-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide-   6-(3-Methyl-4-m-tolyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Methoxy-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Phenyl-pyrrolidine-1-carbonyl)-spiro[2.5]octane-5-carboxylic    acid hydroxyamide;-   6-(4-Isobutyryl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Cyano-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-5-aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide};-   5-Aza-spiro[2.5]octane-6,7-dicarboxylic acid 7-hydroxyamide    6-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide};-   6-[4-(4-Cyano-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   7-(4-Phenyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-6-carboxylic    acid hydroxyamide;-   6-(4-Phenyl-piperidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-Phenyl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Methoxymethyl-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   3-[1-(7-Hydroxycarbamoyl-5-aza-spiro[2.5]octane-6-carbonyl)-piperidin-4-yl]-benzoic    acid methyl ester;-   6-(3-Cyclohexyl-pyrrolidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Isopropyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Isopropyl-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Propyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Ethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Ethyl-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Cyano-2-methyl-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Isopropoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-m-Tolyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-tert-Butyl-phenyl)-piperazine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxy amide;-   6-(4-Pyridin-4-yl-piperazine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Benzyl-piperidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(5-Methoxy-2,3-dihydro-indole-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[5-(2-Methyl-quinolin-4-ylmethoxy)-2,3-dihydro-indole-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   5-Methyl-6-[5-(2-methyl-quinolin-4-ylmethoxy)-2,3-dihydro-indole-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide-   6-(5-Benzyloxy-2,3-dihydro-indole-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2,2-spiroindanepiperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Isopropoxy-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   4-[1-(7-Hydroxycarbamoyl-5-aza-spiro[2.5]octane-6-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methyl-benzoic    acid methyl ester;-   6-[4-(2-Methyl-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(2-Ethyl-phenyl)-piperidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   4-[1-(7-Hydroxycarbamoyl-5-aza-spiro[2.5]octane-6-carbonyl)-piperidin-4-yl]-3-methyl-benzoic    acid methyl ester;-   6-[4-(2,3-Dihydro-benzofuran-5-yl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Isopropyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-methyl-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Phenyl-pyrrolidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Phenyl-pyrrolidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(3-Trifluoromethyl-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(3-Chloro-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(3-Fluoro-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(4-Fluoro-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(4-Chloro-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(4-Trifluoromethyl-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(4-Methoxy-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[3-(4-Phenoxy-phenyl)-pyrrolidine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Cyano-3-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(3-Pyridin-4-yl-pyrrolidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3,5-Dimethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(3-Trifluoromethoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(5-Methoxymethyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(1,4,5,6-Tetrahydro-2H-benzo[f]isoquinoline-3-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-m-Tolyl-piperidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(5-Methoxy-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-[4-(4-Methoxy-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   6-(4-Cyano-4-phenyl-piperidine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid ethyl ester;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid propyl ester;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid isopropyl ester;-   7-Hydroxycarbamoyl-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-5-carboxylic    acid isobutyl ester; and-   6-(5-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-aza-spiro[2.5]octane-7-carboxylic    acid hydroxyamide.    Synthesis

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Green, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

The novel compounds of this invention may be prepared using the reactionpathways and techniques as described below.

A series of compounds of formula 12 are prepared by the methods outlinedin Scheme 1 (where R1 and R2 of formulas 10-12 and R3 and R4 of formulas11-12 correspond to appropriate substituents that would afford compoundsof the invention). H-Asp(OtButyl)-OH was treated with benzyl bromide andDBU in toluene to afford compound 2, which was reacted with 3 to provide4. The N-alkylated product was then treated with NaI in acetone toprovide the corresponding iodide, which was cyclized using LiHMDS in THFto provide the desired product 6. The benzyl protecting group wasswitched to Cbz to afford compound 7. Cyclopropanation of 7 isaccomplished by treating with diazomethane and Pd(OAc)₂ to provide thedesired product 8. The Cbz and Bn groups of 8 were removed byhydrogenation to provide the acid 9. The resulting acid was coupled withamine using standard amide bond formation condition to provide 10.Reductive amination of 10 with aldehyde or ketone to give compound 11.The tert-butyl group was removed by treating with TFA in methylenechloride, followed by direct coupling with hydroxylamine to produce thefinal compound 12.

The synthesis of compounds of formula 7 can also be further achieved byusing the approach outlined in Scheme 2. Both the amino and carboxylicgroup of H-Asp(OtButyl)-OH were protected by benzyl groups to providethe tris benzyl protected amino acid 13. The resulting compound was thentreated with KHMDS, followed by allylation to provide the couplingproduct 14. Dihydroxylation of 14 provide the 1,2-diol 15. The primaryalcohol was then converted to the corresponding mesylate, followed byhydrogenation to give the corresponding cyclized product 17. The aminoand carboxyl group of 17 was reprotected with Cbz and benzyl grouprespectively. Swern oxidation of 18 provides the ketone 19. Using theWittig reaction, compound 19 was converted to the olefin 7.

The synthesis of compounds of general structure 20 is outlined in Scheme3 (where R1 and R2 of formulas 20 and 27 correspond to appropriatesubstituents that would afford compounds of the invention). Diels-Alderreaction of 21 with 22 provide 23. The TMS ether was hydrolyzed to thecorresponding ketone 24. The ketone was then converted to the olefin 25.Cyclopropanation using the similar approach described in scheme 1provides the key intermediate 26. The ethyl ester was directly convertedinto amide 27. The tert-butyl group of 27 was removed to give the acid.The resulting acid was converted to the final product 20 using standardsynthetic conditions.

Alternatively, as shown in Scheme 4 (where R1 and R2 of formulas 28 and29 correspond to appropriate substituents that would afford compounds ofthe invention), the tert-butyl group of compound 26 was removed first,followed by conventional coupling to give amide 28. Basic hydrolysis of28 under refluxing condition provides the acid, the acid was thenconverted to the final compound 29 using the standard couplingprocedure.

The compounds of general structure 30 can be prepared using theprocedure outlined in Scheme 5 (where R1 and R2 of formulas 30 and 32correspond to appropriate substituents that would afford compounds ofthe invention). The ketone 24 was converted into the correspondingdithioketal 31. The ethyl ester group was hydrolyzed to the acid,followed by coupling with amine to provide the amide 32. Following asimilar procedure described in Scheme 3, compound 32 was converted intothe final compound 30.

A series of compounds of formulas 33 and 34 can be prepared followingthe synthesis outlined in Scheme 6 (where R1 and R2 of formulas 33 and34 correspond to appropriate substituents that would afford compounds ofthe invention). Ketone 24 is treated with allyltrimethylsilane in thepresence of TiCl₄ to give 35. Hydroboration followed by oxidationprovide the primary alcohol 36. The primary alcohol was activated andcyclized to the corresponding tetrahydrofuran 37. Conversion of 37 tothe amide and finally hydroxamic acid 33 or 34 proceeds through the sameapproach as previously described.

A series of compounds of formula 38 or 39 are prepared following thesequence outlined in Scheme 7 (where R1 and R2 of formulas 38 and 39correspond to appropriate substituents that would afford compounds ofthe invention). The primary alcohol 36 was oxidized and converted intoolefin. Hydroboration and oxidation provide diol 40. Cyclizationfollowed by a similar sequence as previously described gives 38 or 39.

A series of compounds of formula 41 are prepared following the schemeoutlined in Scheme 8 (where R1 and R2 of formula 41 correspond toappropriate substituents that would afford compounds of the invention).The olefin was treated with MCPBA to provide epoxide 42. The epoxide wastreated with amine to provide the ring-opening product 43. The aminoalcohol was then cyclized to the spiro carbarmate 44. Conversion of 44to the amide and finally hydroxamic acid 41 proceeds through the sameapproach as previously described.

The series of 4-aryl-1,2,3,6-tetrahydro-pyridine of formula 45 and4-aryl-piperidine of formula 46 can be prepared following Scheme 9. Forexample, palladium catalyzed Suzuki coupling of4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester 47 with aryl boronic acid can afford compounds offormula 48 using standard procedures (e.g., Y. Deng, L. Gong, A Mi, H.Liu, Y. Jiang, Synthesis, 2003, 337-339). The Boc protecting group canbe removed by treatment of the corresponding amine with TFA or HCl.Using a standard hydrogenation method,4-aryl-1,2,3,6-tetrahydro-pyridine can be converted to the corresponding4-aryl-piperidine.

The invention is illustrated by the following examples, which are notintended to be limiting in any way.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). Mass spectrometryresults are reported as the ratio of mass over charge, followed by therelative abundance of each ion (in parentheses). In tables, a single m/evalue is reported for the M+H (or, as noted, M−H) ion containing themost common atomic isotopes. Isotope patterns correspond to the expectedformula in all cases.

Example 1(6S,7S)—N-hydroxy-5-methyl-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamideStep 1a. Preparation of BnNH-L-Asp(O^(t)butyl)-OBn

To a mixture of H-L-Asp(O^(t)Butyl)-OH (22 g, 106 mmol) and benzylbromide (35 g, 205 mmol) in toluene (600 mL) was added DBU (33 g, 217mmol). The mixture was stirred at RT for overnight, and was filtered.The filtrate was concentrated. The residue was purified by Combiflash(hexane and ethyl acetate: gradient 0 to 10% in 12 min) to afford 12.1 g(30.9%) of the desired product BnNH-L-Asp(O^(t)butyl)-OBn. MS (ESI):370.3 (M+H⁺).

Step 1b. Preparation of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(chloromethyl)prop-2-en-1-yl]amino}succinate

A mixture of BnNH-L-Asp(O^(t)butyl)-Obn from step 1a (12.1 g, 32.6mmol), K₂CO₃ (14 g, 3 eq.), NaI (3.0 g, 20 mmol) and1-chloro-2-chloromethyl-1-propene (5.1 g, 40.8 mmol) in MeCN (150 mL)was stirred at 81° C. for 16 h. After cooling, the mixture was filtered.The filtrate was concentrated and purified by Combiflash (hexane andethyl acetate: gradient 0 to 8% during 12 min) to give (8.7 g) 1-benzyl4-tert-butyl(2S)-2-{benzyl[2-(chloromethyl)prop-2-en-1-yl]amino}succinate, MS (ESI):458.3/460.3 (M+H⁺).

Step 1c. The preparation of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate

A mixture of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(chloromethyl)prop-2-en-1-yl]amino}succinate from step1b (8.7 g) and NaI (8.0 g) in acetone (100 mL) was stirred at RTovernight. The solid was filtered off and the filtrate concentrated. Theresidue was treated with methylene chloride and filtered through a padof silica gel to give 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate (9.2 g). MS(ESI): 550.2 (M+H⁺).

Step 1d. Preparation of 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate

To a cooled (−78° C.) solution of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate from step 1c(9.2 g) in THF (50 mL) was added dropwise LiHMDS (1.0 M in THF, 20.2 mL)at −78° C. during a period of 30 min. The mixture was stirred at −78° C.for 1 h, and then was allowed to warm to −30° C. during 3 h. Thereaction mixture was quenched with 10% citric acid (10 mL) and dilutedwith brine (100 mL). The mixture was extracted with ethyl acetate (4×75mL). The combined organic layers were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified through Combiflash(hexane and ethyl acetate: gradient 0 to 5% during 12 min) to give thedesired 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate (3.45 g). MS(ESI): 422.3 (M+H⁺).

Step 1e. Preparation of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate

A mixture of 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate from step 1d(2.3 g) and benzyl chloroformate (3 mL) was stirred at 65° C. for 28 h.The excess of the benzyl chloroformate was removed under reducedpressure. The residue was purified through Combiflash (hexane and ethylacetate: gradient 0 to 10% during 12 min) to give the desired compound1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (1.40 g). MS (ESI):488.1 (M+Na⁺); 366.1 (M+H⁺—COO(t-Bu)).

Step 1f Preparation of 5,6-dibenzyl 7-tert-butyl(6S,7S)-5-azaspiro[2.5]octane-5,6,7-tricarboxylate

A solution of Diazald (5.0 g) in ethyl ether (50 mL) was added dropwiseto a mixture of KOH (2.65 g), di(ethylene)ethyl ether (5 mL), water (4mL) and ethyl ether (5 mL) at 60° C. The diazomethane formed wasdirectly distilled into a reaction flask which contained a mixture of1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate of step 1e (4.0 g)and palladium(II) acetate (50 mg) in ethyl ether (30 mL) at −20° C. Thereaction mixture was allowed to warm to RT and stirred for 3 h. Themixture was filtered and concentrated. The residue was purified throughCombiflash to afford compound 5,6-dibenzyl 7-tert-butyl(6S,7S)-5-azaspiro[2.5]octane-5,6,7-tricarboxylate (3.86 g). MS (ESI):502.3 (M+Na⁺); 380.3 (M+H+—COO(t-Bu)).

Step 1 g. Preparation of(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid

5,6-dibenzyl 7-tert-butyl(6S,7S)-5-azaspiro[2.5]octane-5,6,7-tricarboxylate (2.0 g) washydrogenated in methanol (100 mL) with 5% Pd—BaSO₄ (750 mg) under ahydrogen atmosphere (hydrogen-balloon) at RT. The catalyst was removedby filtration. The filtrate was concentrated. The residue was driedunder reduced pressure to produce(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid(1.06 g). MS (ESI): 256.1 (M+H⁺); 200.1 (M+H⁺-t-Bu).

Step 1h. Preparation of Bn₂N-L-Asp(O^(t)Butyl)-OBn

To a suspension of L-aspartic acid β-tert-butyl ester (12.5 g, 66 mmol)in DMF (100 ml) and DMSO (25 mL) was added benzyl bromide (39.5 mL, 236mmol) followed by K₂CO₃ (27.5 g, 198 mmol). The mixture was stirred at50° C. overnight. After cooling to room temperature, the salts werefiltered and the filtrate was reduced to a small volume by evaporationunder reduced pressure. The residue was diluted with water (200 mL) andthe resulting solution was extracted with EtOAc three times. Thecombined organic solution was washed with brine three times, dried byMgSO₄ and concentrated. The residue was purified on silica gel using 10%EtOAc/Hexane as elution to provide 25.1 g of Bn₂N-L-Asp-(O^(t)Butyl)-OBn(83%). MS (ESI): 460.1 (M+H⁺).

Step 1i: Preparation of 4-benzyl 1-tert-butyl(3S)-2-allyl-3-(dibenzylamino)succinate

To a solution of Bn₂N-L-Asp-(O^(t)Butyl)-Obn from step 1h (9.7 g, 21.1mmol) in anhydrous THF (100 mL) at −78° C. was added 0.5 M solution ofKHMDS in toluene (50.7 mmol). After stirring at −78° C. for one hour,allyl iodide (2.9 mL, 31.7 mmol) was added. The temperature wasincreased to −30° C. and stirring was continued at this temperature forabout 4 hrs. The reaction was quenched with 10% citric acid solutionfollowed by diluting with a small amount of brine. The resultingsolution was extracted with AcOEt three times. The combined solution waswashed with brine three times, dried by MgSO₄ and concentrated. Theresidue was purified on silica gel using 20% EtOAc/Hexane as elution toprovide a mixture of cis and anti-product 4-benzyl 1-tert-butyl(3S)-2-allyl-3-(dibenzylamino)succinate (8.1 g, 77%). MS (ESI): 500.1(M+H⁺).

Step 1j: Preparation of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate

To a suspension of a mixture of cis and anti-product 4-benzyl1-tert-butyl (3S)-2-allyl-3-(dibenzylamino)succinate from step 1i (3 g,6.0 1 mmol) in acetone and water (10 mL, 1:1 v/v) at 0° C. was added NMO(0.774 g, 6.61 mmol). The suspension was stirred at 0° C. for one hour,then a solution of OsO₄ (4%) in water (0.15 mL) was added. Thesuspension was stirred at room temperature overnight. To the reactionsuspension was added sodium hydrosulfite (90 mg) and stirred about 1hour. The reaction suspension was filtered through Celite. The filtratewas extracted with EtOAc three times and the combined organic solutionwas washed with brine, dried by MgSO₄ and concentrated. The residue waspurified on silica gel using 50% EtOAc/Hexane as elution to providedesired 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate (1.78 g,56%). MS (ESI): 534.2 (M+H⁺).

Step 1k: Preparation of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate

1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate from step 1j(2.917 g, 5.47 mmol) was dissolved in pyridine (10 mL), cooled to 0° C.and MsCl (0.444 mL, 5.74 mmol) was added. The solution was stirred at 0°C. for 4 hours and diluted by 10% citric acid. The reaction mixture wasextracted with EtOAc three times. The combined organic solution waswashed by 10% citric acid three times, then brine, dried with MgSO₄ andconcentrated, the residue was purified on silica gel using 50%EtOAc/Hexane as elution to provide of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate(2.696 g, 81%). MS (ESI): 612.1.1 (M+H⁺).

Step 1l. Preparation of(2S,3S)-3-(tert-butoxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid

To a solution of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinatefrom step 1k (5.02 g, 8.2 mmol) in methanol (40 mL) was added Pd-Blackand 1M HCl (4 mL) solution. The mixture was hydrogenated under H₂ at 50psi overnight. The catalyst was filtered off and the solution wasconcentrated to dryness. The residue was dissolved in ethanol andtriethyl amine (2 mL) was added. The solution was refluxed for threehours and then concentrated to dryness to provide the crude compound(2S,3S)-3-(tert-butoxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid,the compound was directly used in the next step. MS (ESI): 189.9(M+H⁺-t-Bu); 246.0 (M+H⁺); 268.0 (M+Na⁺).

Step 1m. Preparation of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate

To a solution of(2S,3S)-3-(tert-butoxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid(2.02 g, crude from the previous step 1l in DMF was addedN-(benzyloxycarbonyloxy)-succinimide (3.08 g, 12.36 mmol) followed byNMM (2.71 mL, 24.7 mmol). The mixture was stirred at room temperatureovernight. The solution was acidified to a pH of 1 with 1 M HCl,extracted with EtOAc and the organic phase was washed with brine threetimes, dried by MgSO₄ and concentrated. The residue was purified onsilica gel using 10% MeOH/CH₂Cl₂ as elution solvent to provide a crudemixture (2.17 g, 70%). MS (ESI): 280.0 (M+H⁺—COO(t-Bu)); 402.0 (M+Na⁺).

To the above material (1.28 g, 3.38 mmol) in benzene (15 mL) was addedbenzyl bromide (0.68 mL, 5.75 mmol) followed by DBU (1.01 mL, 6.76mmol). The mixture was stirred at room temperature overnight. Then EtOAcwas added. The solution was washed with 10% citric acid three times,then with brine, dried over MgSO₄ and then concentrated. The residue waspurified on silica gel using 40% EtOAc/Hexane as elution solvent toprovide of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate (0.96 g, 61%). MS(ESI): 370.0 (M+H⁺—COO(t-Bu)); 492.0 (M+Na⁺).

Step 1n. Preparation of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate

To a cooled solution of oxalyl chloride (315 mg) in methylene chloride(2.5 mL) was added dropwise a solution of DMSO (0.30 mL) in methylenechloride (3.0 mL) at −78° C. The mixture was stirred at −78° C. for 30min, 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate of step 1m (900 mg) inmethylene chloride (4 mL) was added dropwise. The mixture was stirred at−78° C. to −60° C. for 1 h. Triethylamine (620 mg) in methylene chloride(2.5 mL) was added. The mixture was allowed to warm to RT during aperiod of 2 h. The mixture was diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was flashchromatographed on silica gel column to afford 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate (570 mg). MS (ESI): 490.3(M+Na⁺); 368.2 (M+H⁺—COO(t-Bu)).

Step 1o: Preparation of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate

To a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate of step 1n (850 mg) intoluene (10 mL) was added dropwise a solution of Ph₃P═CH₂ (0.25M intoluene/THF (3:1), 9.1 mL) at −10° C. The mixture was stirred andallowed to warm to RT during a period of 2 h. The mixture was dilutedwith ethyl acetate (75 mL) and washed with brine (3×25 mL). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was flash chromatographed on silica gel column to afford1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (546 mg). MS (ESI):488.1 (M+Na+); 366.1 (M+H⁺—COO(t-Bu)).

Step 1p: Preparation of tert-butyl(6S,7S)-5-methyl-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxylate

A mixture of(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acidof step 1 g (25 mg), BOP (45 mg), 1-(3-methylphenyl)piperazine (176 mg)and di-isopropylethylamine (70 μL) in DMF (500 μL) was stirred at RTovernight. Formaldehyde solution (0.5 M in THF/MeCN (1:1), 600 μL) wasadded to the mixture followed by NaBH(OAc)₃ (0.25 M in THF/MeCN (1:1),1000 μL). The resulting mixture was stirred overnight. The solvents wereremoved under reduced pressure. The residue was dissolved in ethylacetate (5 mL). The solution was washed with NaHCO₃ (7.5%, 3×1 mL). Theorganic phase was dried over MgSO₄ and filtered and concentrated. Theresidue was used directly in the next step reaction without furtherpurification.

Step 1q: Preparation of(6S,7S)—N-hydroxy-5-methyl-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

The crude product from step 1p was dissolved in methylene chloride (3mL). To the solution was added TFA (3 mL) followed by water (0.15 mL).The mixture was stirred at RT overnight and was concentrated underreduced pressure. The residue was dissolved in DMF (200 μL). To thesolution was added BOP (45 mg) and hydroxylamine (21 mg). The mixturewas adjusted to pH: 9 with di-isopropylethylamine (˜80 μL), and stirredat RT for overnight, and direct RP-HPLC purification to afford the finalproduct(6S,7S)—N-hydroxy-5-methyl-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide.Ms(ESI): (M+H)+=387.1

Example 2(6S,7S)—N-hydroxy-5-methyl-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=373.2

Example 3(6S,7S)—N-hydroxy-5-methyl-6-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=441

Example 4(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=387.1

Example 5(6S,7S)-6-{[4-(4-chlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=407.1

Example 6(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=432.0

Example 7(6S,7S)—N-hydroxy-5-methyl-6-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=372.2

Example 8(6S,7S)—N-hydroxy-6-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388

Example 9(6S,7S)—N-hydroxy-5-methyl-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=370.0.

Example 11(6S,7S)—N-hydroxy-5-methyl-6-[(4-quinolin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=424.3

Example 12(6S,7S)-6-{[4-(2,3-dichlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=441

Example 13(6S,7S)—N-hydroxy-5-methyl-6-[(4-quinolin-4-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=424.3

Example 14(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methylquinolin-4-yl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=438.4

Example 15(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-phenylethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=401.3

Example 16(6S,7S)—N-hydroxy-5-methyl-6-[(4-pyridin-4-ylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=373.3

Example 17(6S,7S)—N-hydroxy-5-methyl-6-{[4-(4-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=418.3

Example 18(6S,7S)—N-hydroxy-6-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=403

Example 19(6S,7S)—N-hydroxy-5-methyl-6-[(4-phenoxypiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388.3

Example 20(6S,7S)-6-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=344.3

Example 21(6S,7S)-6-(4,7-dihydrothieno[2,3-c]pyridin-6(5H)-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=350.2

Example 22(6S,7S)-6-[(3-benzylpyrrolidin-1-yl)carbonyl]-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=372.3.

Example 23(6S,7S)—N-hydroxy-5-methyl-6-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=374.2

Example 24(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-pyridin-4-ylethyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=401.3

Example 25(6S,7S)—N-hydroxy-5-methyl-6-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=442.3

Example 26(6S,7S)—N-hydroxy-5-methyl-6-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=442.3

Example 27(6S,7S)-6-(1,4′-bipiperidin-1′-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=379.3

Example 28(6S,7S)—N-hydroxy-5-methyl-6-{[4-(pyridin-2-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388.3

Example 29(6S,7S)—N-hydroxy-5-methyl-6-{[4-(pyridin-4-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388.3

Example 30(6S,7S)—N-hydroxy-5-methyl-6-{[4-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388.3

Example 31(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamideStep 1. Preparation of 4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine

To a solution of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(500 mg, 1.51 mmol), Na₂CO₃ (2.1 mL, 2.0 M), LiCl (188 mg) and Pd(PPh₃)₄12 mg) was added 2-methylphenylboronic acid. The reaction mixture wasrefluxed for 2.0 hours, and cooled to room temperature. The solution wasextracted with ethyl acetate and washed by 2N Na₂CO₃ and NH₄OH solutionand saturated brine. The crude residue was purified by flash column togive 370 mg of the pure compound.

The above material was dissolved in 4.5 mL CH₂Cl₃ and 0.5 mL H₂O,followed by addition of 5 mL of TFA. The mixture was stirred at RT for50 min. The mixture was then concentrated to give the correspondingmaterial.

Step 2. Preparation of(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

1,4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine was coupled to(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acidusing procedures analogous to those for example 1 to give the desired(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamideMs(ESI): (M+H)+=384.1.

Example 32(6S,7S)—N-hydroxy-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=373.1

Example 33(6S,7S)—N-hydroxy-5-methyl-6-(1,3,4,9-tetrahydro-2H-3-carbolin-2-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=383.0.

Example 34(6S,7S)—N-hydroxy-5-methyl-6-[(9-methyl-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=396.9.

Example 35(6S,7S)-6-{[4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=388.0

Example 36(6S,7S)-6-{[4-(2-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=404.0

Example 37(6S,7S)-6-{[4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=415.1.

Example 38(6S,7S)-6-{[4-phenyl-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=356

Example 39(6S,7S)-6-{[4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=418.0

Example 40(6S,7S)—N(7)-hydroxy-N(6),5-dimethyl-N(6)-(3-phenylpropyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=360.1

Example 41(6S,7S)—N(7)-hydroxy-N(6)-isobutyl-5-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=284.0

Example 42(6S,7S)—N-hydroxy-5-methyl-6-{[4-(2-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=418.0

Example 43(6S,7S)—N(7)-hydroxy-N(6)-isobutyl-N(6),5-dimethyl-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=298.0

Example 44(6S,7S)—N(7)-hydroxy-5-methyl-N(6)-(2-phenoxyethyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=348.0

Example 45(6S,7S)—N(7)-hydroxy-N(6)-[2-(4-methoxyphenyl)ethyl]-5-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=362.0

Example 46(6S,7S)—N(7)-hydroxy-5-methyl-N(6)-(4-phenylbutyl)-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=360.0

Example 47(6S,7S)—N(7)-hydroxy-5-methyl-N(6)-[3-(2-oxopyrrolidin-1-yl)propyl]-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=353.0

Example 48(6S,7S)—N-hydroxy-5-methyl-6-[(10aR)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-ylcarbonyl]-5-azaspiro[2.5]octane-7-carboxamide

Step 1. Preparation of methyl{[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate

To a solution of (2R)-indoline-2-carboxylic acid (1 g, 5.64 mmol) andHCl salt of amino-acetic acid methyl ester (710 mg, 5.64 mmol) and BOP(2.75 g, 1.1 eq) in 15 mL DMF was added 2.95 mL hunig base. The mixturewas stirred overnight. The mixture was diluted in sat. NaHCO₃, extractedwith EtOAc three time, and washed with sat. NaHCO₃ and brine. Theorganic solution was dried over Na₂SO₄ and concentrated to give thedesired methyl {[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate.The material was used directly in the next step without furtherpurification.

Step 2. Preparation of(10aR)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

methyl {[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate (390 mg)was mixed with 100 mg of NaOMe in 5 mL of Ethanol. The mixture wasrefluxed for 2 hours and cooled to RT. The crude material was purifiedby flash chromatography to give the desired(10aR)-2,3,10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione.

To a solution of(10aR)-2,3,10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione (200 mg,0.99 mmol) in 5 mL THF was added LAH. The reaction mixture was refluxedfor 1 h. Standard work up afforded 170 mg of pure(10aR)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole.

Step 3

Using the procedure described in Ex. 1,(10aR)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole was converted tothe desired(6S,7S)—N-hydroxy-5-methyl-6-[(10aR)-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-ylcarbonyl]-5-azaspiro[2.5]octane-7-carboxamide.Ms(ESI): (M+H)+=385.0.

Example 49(5,6-trans)-N-hydroxy-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamide

Step 1. Preparation of 2-tert-butyl 1-ethyl(1,2-trans)-4-[(trimethylsilyl)oxy]cyclohex-4-ene-1,2-dicarboxylate

At −20° C., a 0.4 M solution in toluene of methyl aluminumbis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) (50 mL, 20 mmole) wasadded to solvent methylenechloride (15 ml) slowly with stirring. At thistemperature, a solution of tert-butyl ethyl fumarate (3.60 g, 18 mmole)in methylenechloride (4 mL) was added to MAD solution slowly withstirring. At −20° C., to the reaction mixture, a solution of2-trimethylsilyloxy-1,3-butadiene (2.56 g, 18 mmole) inmethylenechloride (4 mL) was added slowly. The reaction mixture wasstirred at −20° C. for 70 hours. The reaction mixture was quenched withsaturated citric acid solution, and diluted with methylenechloride. Someinsoluble material came out and was filtered off. After separation, theaqueous layer was extracted with methylenechloride (×2). The combinedextracts were dried over Na₂SO₄. After filtration, the filtrate wasconcentrated. The resulting residue was purified by flashchromatography, 4.12 g pure product was obtained. The filtrate wasre-purified by column chromatography. Another 0.56 g pure product wasobtained. And 0.78 g starting material tert-butyl ethyl fumarate wasrecovered. Yield: 97%.

Step 2. Preparation of 2-tert-butyl 1-ethyl(1,2-trans)-4-oxocyclohexane-1,2-dicarboxylate

The compound 2-tert-butyl 1-ethyl(1,2-trans)-4-[(trimethylsilyl)oxy]cyclohex-4-ene-1,2-dicarboxylate ofstep 1(0.72 g, 2.1 mmol) was dissolved in methanol (10 ml). To thesolution, saturated citric acid solution (1 mL) was added. The mixturewas stirred at r.t. for 4 hours. TLC showed starting material wasconsumed. Methanol was removed by rotavaporation. The resulting residuewas taken up into ethyl acetate and washed with water (×1), brine (×1),dried over Na₂SO₄. After filtration, the filtrate was concentrated toyield quantitative product.

Step 3. Preparation of 2-tert-butyl 1-ethyl(1,2)-4-methylenecyclohexane-1,2-dicarboxylate

To the mixture of methyl triphenylphosponium bromide (0.87 g, 2.4 mmole)in toluene (6 mL) and THF (2 mL), 1 M of NaHMDS (2.4 mL, 2.4 mmole) inTHF was added. The mixture was stirred at r.t. for 1.5 hour. Thismixture was added to a pre-cold (−10° C.) solution of compound2-tert-butyl 1-ethyl (1,2-trans)-4-oxocyclohexane-1,2-dicarboxylate ofstep 2 (0.57 g, 2.1 mmol) in toluene (8 mL) slowly with stirring. Aftercompletion of addition, the reaction mixture was stirred at −10° C. for10 mins, then, at r.t. for 1.5 hour. TLC showed starting materialconsumed. The reaction mixture was diluted with ethyl acetate, washedwith water (×1); brine (×2); dried over Na₂SO₄. After filtration, thefiltrate was concentrated. The resulting residue was purified by flashchromatography. 0.56 g of 2-tert-butyl 1-ethyl(1,2)-4-methylenecyclohexane-1,2-dicarboxylate was obtained. Yield: 99%.

Step 4. Preparation of 5-tert-bul 6-ethyl(5,6-trans)-spiro[2.5]octane-5,6-dicarboxylate

To a solution of KOH (5 g) in water (8 mL), di(ethylene glycol) ethylether (24 mL), and ethyl ether (25 mL) in flask A, 3 g of diazald wasadded in three portions. After the addition of first portion of diazald,the flask was put into a pre-heated (at 60° C.) oil bath in order todistill out CH₂N₂ formed with ether to another flask (B) pre-chilled toaround −15° C. and containing 2-tert-butyl 1-ethyl(1,2)-4-methylenecyclohexane-1,2-dicarboxylate ster from step 3 (500mg), and Pd(OAc)₂ (80 mg) in ether (15 ml). After 5 minutes, the oilbath was removed from flask A. Then, the second portion of diazald wasadded, and the above procedure repeated twice. After completion of thedistillation of CH₂N₂ with ether into flask B, the cold bath was removedfrom flask B. The reaction mixture was stirred at r.t. for 2 hours thenfiltered through silica gel, rinsed with ethyl acetate and thenmethylenechloride. The filtrate was concentrated. The resulting residuewas treated according to the above described procedures three additionaltimes. Normal work up afforded 5-tert-butyl 6-ethyl(5,6-trans)-spiro[2.5]octane-5,6-dicarboxylate (80% yield).

Step 5. Preparation of(5,6-trans)-6-(ethoxycarbonyl)spiro[2.5]octane-5-carboxylic acid

5-tert-butyl 6-ethyl (5,6-trans)-spiro[2.5]octane-5,6-dicarboxylate (150mg, 0.53 mmol) was dissolved in a solution of methylene chloride (2mL)-TFA (2 mL) and water (0.1 mL). The mixture was stirred at r.t. for 3hours. TLC showed that starting material was consumed. The reactionmixture was concentrated to yield quantitative product(5,6-trans)-6-(ethoxycarbonyl)spiro[2.5]octane-5-carboxylic acid.

Step 6. Preparation of ethyl(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxylate

(5,6-trans)-6-(ethoxycarbonyl)spiro[2.5]octane-5-carboxylic acid of step5 (27.4 mg, 0.12 mmol) and 1-(2-methyl-4-nitrophenyl)-piperazine (29.4mg, 0.13 mmol) were dissolved in DMF (1 mL). To the resulting solution,BOP reagent (56.3 mg, 0.127 mmol) was added. After stirring 10 minutes,DIEA was added to the mixture. It was stirred at r.t. overnight thenquenched with saturated citric acid solution. The product was extractedwith ethyl acetate. The extract was washed with water (×1), brine (×1);dried over Na₂SO₄. After filtration, the filtrate was concentrated toafford ethyl(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxylate.

Step 7. Preparation of compound(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxylicacid

ethyl(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]-octane-6-carboxylateobtained from step 6 was mixed in THF (2 mL)-water (0.4 mL) and LiOH.H₂O(200 mg) and heated at reflux for 36 hours. After cooling, the reactionmixture was neutralized with saturated citric acid and extracted withethyl acetate (×3). The combined extracts were washed with citric acid(×1), brine (×1), and dried over Na₂SO₄. After filtration, the filtratewas concentrated to give(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxylicacid.

Step 8. Preparation of compound(5,6-trans)-N-hydroxy-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamide

To a solution of(5,6-trans)-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxylicacid obtained in step 7 and hydroxylamine HCl salt (30 mg, 4.3 mmol) in1 mL DMF was added BOP coupling agent (56.3 mg, 0.13 mmol). Afterstirring for 10 minutes, DIEA was added to the mixture. The mixture wasstirred at r.t. overnight and monitored by HPLC. The final desiredproduct was purified by RP-HPLC to give 25.6 mg of(5,6-trans)-N-hydroxy-5-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamidein 50% yield in three steps. Ms(ESI): (M+H)+=417.2

Example 50(5,6-trans)-N-hydroxy-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous to those forexample 49. Ms(ESI): (M+H)+=372.2

Example 51(5,6-trans)-N-hydroxy-5-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-6-carboxamide

This compound was prepared using procedures analogous to those forexample 49. Ms(ESI): (M+H)+=355.

Example 52(5,6-trans)-N-hydroxy-5-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-6-carboxamide

This compound was prepared using procedures analogous to those forexample 49. Ms(ESI): (M+H)+=372.0

Example 53(5,6-trans)-N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous to those forexample 49. Ms(ESI): (M+H)+=355.

Example 54(6S,7S)—N-hydroxy-6-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 48. Ms(ESI): (M+H)+=371.2.

Example 55(6S,7S)-6-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-ylcarbonyl)-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 48. Ms(ESI): (M+H)+=399.4.

Example 56 Methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=414.0.

Example 57 Benzyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=490.0

Example 58(6S,7S)—N-Hydroxy-5-(methylsulfonyl)-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=434.0.

Example 59(6S,7S)—N-hydroxy-6-{[3-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=402.4.

Example 60(6S,7S)—N-hydroxy-5-methyl-6-{[3-(2-phenylethyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=386.0.

Example 61(6S,7S)—N-hydroxy-6-{[4-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=402.4.

Example 62(6S,7S)-6-{[4-[3-(aminocarbonyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=398.9.

Example 63(6S,7S)—N-hydroxy-6-{[4-(2-methoxyphenyl)piperidin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=402.4.

Example 64(6S,7S)-6-{[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=391.3.

Example 65(6S,7S)—N-hydroxy-6-{[4-(2-methyl-3-nitrophenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=418.3.

Example 66(6S,7S)-6-(3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=357.4.

Example 67(6S,7S)—N(7)-hydroxy-N(6)-(4-methoxyphenyl)-N(6)-methyl-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=334.

Example 68(6S,7S)—N-hydroxy-6-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=403.0.

Example 69(6S,7S)-6-{[4-(3-chlorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=407.3.

Example 70(6S,7S)—N-hydroxy-6-[(4-phenyl-1,4-diazepan-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=373.

Example 71(6S,7S)—N-hydroxy-6-{[3-methyl-4-(3-methylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=387.

Example 72(6S,7S)—N-hydroxy-6-{[4-(3-methoxyphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=388.4.

Example 73(5S,6S)—N-hydroxy-6-[(3-phenylpyrrolidin-1-yl)carbonyl]spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=343.3.

Example 74(6S,7S)—N-hydroxy-6-[(4-isobutyrylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=353.

Example 75(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=395.

Example 76(6S,7S)—N(7)-Hydroxy-5-methyl-N(6)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.5]octane-6,7-dicarboxamideStep 1. Preparation of 4-(2-methylquinolin-4-ylmethoxy)phenylamine

To a mixture of 2-methylquinoline (43.0 g, 0.3 mol), iron (5.04 g, 0.09mol), FeSO₄.7H₂O (25.0 g, 0.09 mol) in methanol (400 mL) and water (200mL) was added sulfuric acid (conc., 16.0 mL, 0.3 mol) at 0° C., and thenH₂O₂ (160 mL) was slowly added at 0° C. The mixture was then warmed toroom temperature and stirred overnight. The solution was diluted withwater, basified with ammonium hydroxide, and extracted with ethylacetate. The combined extract was washed with brine, dried andconcentrated. Recrysatllization from ethyl ether/hexane to give(2-Methylquinolin-4-yl)methanol_(12.0 g). ESI (M+H)⁺173.9.

(2-Methylquinolin-4-yl)methanol (7.0 g) was dissolved in chloroform (150mL) and cooled to 0° C., the thionyl chloride (15.0 mL) was slowly addedat this temperature and then the reation mixture was allowed to warm upto room temperature while stirring overnight. The solvent was removedand the residue was triturated with ethyl acetate/ethyl ether to providethe compound 4-chloromethyl-2-methylquinoline as the HCl salt (9.0 g).ESI (M+H)⁺191.9.

The mixture of 4-chloromethyl-2-methylquinoline (6.84 g, 30.0 mmol),(4-hydroxyphenyl)carbamic acid tert-butyl ester (6.24 g, 30.0 mmol),Cs₂CO₃ (20.0 g, 60.0 mmol), and n-Bu₄NI (11.1 g, 30.0 mmol) in DMSO (150mL) was stirred at 80° C. for 3 h. The mixture was then cooled, dumpedinto cold water, and extracted with ethyl acetate. The combined extractwas washed with water, brine, dried and concentrated. Chromatograph byCH₂Cl₂/EtOAc to provide compound[4-(2-methylquinolin-4-ylmethoxy)phenyl]-carbamic acid tert-butyl ester(8.0 g). ESI (M+H)⁺365.3.

To a solution of compound[4-(2-methylquinolin-4-ylmethoxy)phenyl]carbamic acid tert-butyl ester(1.5 g) in ethyl acetate (5 mL) was added 4 N HCl in dioxane (20 mL) andthe mixture was stirred at room temperature for 3 h. Ethyl ether wasadded and the precipitate was filtered and washed with ethyl ether toprovide 4-(2-methylquinolin-4-ylmethoxy)phenylamine as an HCl salt (1.3g). ESI (M+H)⁺265.0.

Step 2. Preparation of tert-butyl(6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate

4-(2-Methylquinolin-4-ylmethoxy)phenylamine as an HCl salt (94.0 mg,0.28 mmol) and(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid(70.0 mg, 0.27 mmol) were dissolved in DMF (2.0 mL). BOP (143.0 mg, 0.32mmol) was added to the above solution and then cooled to 0° C.Diisopropylethylamine (0.175 mL, 1.0 mmol) was added to the abovemixture at 0° C. and then the reaction was stirred at room temperaturefor 2 h. The mixture was diluted with water, extracted with ethylacetate, the combined extract was washed with brine, dried andconcentrated. The crude tert-butyl(6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate(140 mg) was used in the next step without purification. ESI(M+H)⁺502.4.

Step 3. Preparation of tert-butyl(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate

To a solution of tert-butyl(6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate(140 mg, 0.27 mmol) in methanol (3.0 mL) was added formaldehyde (37%solution in water, 0.5 mL) and sodium triacetoxyborohydride (0.25 g, 1.2mmol). The mixture was then stirred at room temperature for 2 h. Thereaction was diluted with ethyl acetate, washed with saturated NaHCO₃,water and brine. Dried and concentrated. tert-butyl(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate(105.0 mg) was obtained by column using CH₂Cl₂/Methanol (10%). ESI(M+H)⁺516.5.

Step 4. Preparation of(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylicacid

TFA (1.0 mL) was added to a solution of tert-butyl(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate(105.0 mg) in CH₂Cl₂ (1.0 mL) and the mixture was stirred at roomtemperature for 5 h. The solvent was removed to provide(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylicacid (140 mg) as an TFA salt. ESI (M+H)⁺460.3.

Step 5. Preparation of(6S,7S)—N(7)-hydroxy-5-methyl-N(6)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.5]octane-6,7-dicarboxamide

To BOP (120.0 mg, 0.24 mmol) was added to a solution of(6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylicacid (140 mg, 0.20 mmol) in DMF (1.0 mL) at 0° C. followed byhydroxylamine hydrochloride (28.0 mg, 0.40 mmol). 4-methylmorpholine(0.07 mL, 0.70 mmol) was then added to the above mixture at 0° C. andstirred at this temperature for 2 h. The product (70 mg) was purified bypreparative HPLC. ESI (M+H)⁺475.4.

Example 77(6S,7S)—N(7)-Hydroxy-N(6)-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.5]octane-6,7-dicarboxamide

This compound was prepared using procedures analogous to those forexample 77. Ms(ESI): (M+H)+=461.0.

Example 78(6S,7S)-6-{[4-(4-cyanophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=384.0.

Example 79(6S,7S)—N-hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-6-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.0.

Example 80(6S,7S)—N-hydroxy-6-[(4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.

Example 81(6S,7S)—N-Hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=359.4.

Example 82(6S,7S)—N-hydroxy-6-({4-[3-(methoxymethyl)phenyl]piperidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=402.

Example 83

Methyl3-[1-({(6S,7S)-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]benzoate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=416.

Example 84(6S,7S)-6-[(3-Cyclohexylpyrrolidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=350.4.

Example 85(6S,7S)—N-Hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=398.4.

Example 86(6S,7S)—N-hydroxy-6-{[4-(3-isopropylphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

(6S,7 S)—N-hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide (10 mg) washydrogenated at 1.0 atm over BaSO₄ in MeOH for one hour to give thedesired product, Ms(ESI): (M+H)+=400.4.

Example 87(6S,7S)—N-hydroxy-6-{[4-(4-propylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=398.

Example 88(6S,7S)—N-hydroxy-6-{[4-(4-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=384.4.

Example 89(6S,7S)—N-Hydroxy-6-{[4-(4-ethylphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=386.

Example 90(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=398.

Example 91(6S,7S)—N-Hydroxy-6-{[4-(3-isopropoxyphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=414.4.

Example 92(6S,7S)—N-Hydroxy-6-{[4-(3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=370.3.

Example 93(6S,7S)—N-Hydroxy-6-{[4-(3-methylphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=372.4.

Example 94(6S,7S)-6-{[4-(4-tert-butylphenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=415.4.

Example 95(6S,7S)—N-Hydroxy-6-[(4-pyridin-4-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=360.

Example 96(6S,7S)-6-[(3-Benzylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=371.9.

Example 97(6S,7S)—N-hydroxy-6-[(5-methoxy-2,3-dihydro-1H-indol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms(ESI): (M+H)+=346.3.

Example 98(6S,7S)—N-hydroxy-6-({5-[(2-methylquinolin-4-yl)methoxy]-2,3-dihydro-1H-indol-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms(ESI): (M+H)+=487.4.

Example 99(6S,7S)—N-hydroxy-5-methyl-6-({5-[(2-methylquinolin-4-yl)methoxy]-2,3-dihydro-1H-indol-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms(ESI): (M+H)+=501.4.

Example 100(6S,7S)-6-{[5-(benzyloxy)-2,3-dihydro-1H-indol-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 76. Ms(ESI): (M+H)+=422.3.

Example 101(6S,7S)-6-(1,3-dihydro-1′H-spiro[indene-2,4′-piperidin]-1′-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=384.4.

Example 102(6S,7S)—N-hydroxy-6-{[4-(3-isopropoxyphenyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=416.4.

Example 103

Methyl4-[1-({(6S,7S)-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methylbenzoate

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=427.9.

Example 104(6S,7S)—N-hydroxy-6-{[4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=414.8.

Example 105(6S,7S)-6-{[4-(2-ethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=385.9.

Example 106

Methyl4-[1-({(6S,7S)-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]-3-methylbenzoate

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=429.9.

Example 107(6S,7S)-6-{[4-(2,3-dihydro-1-benzofuran-5-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=412.2.

Example 108(6S,7S)—N-hydroxy-6-{[4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=412.25.

Example 109(6S,7S)—N-Hydroxy-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=344.1.

Example 110(6S,7S)—N-Hydroxy-6-{[(3S)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=344.1.

Example 112(6S,7S)—N-hydroxy-6-({3-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=412.1.

Example 113(6S,7S)-6-{[3-(3-chlorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=378.1.

Example 114(6S,7S)-6-{[3-(3-fluorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=362.1.

Example 115(6S,7S)-6-{[3-(4-fluorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=362.1.

Example 116(6S,7S)-6-{[3-(4-chlorophenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=378.1.

Example 117(6S,7S)—N-hydroxy-6-({3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl}carbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=412.1.

Example 118(6S,7S)-6-{[3-(4-methoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=374.1.

Example 119(6S,7S)-6-{[3-(4-phenoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=436.2.

Example 120(6S,7S)—N-hydroxy-6-{[4-(3-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=386.1.

Example 121(6S,7S)—N-hydroxy-6-{[4-(4-cyano-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=395.1.

Example 122(6S,7S)-6-{[3-(3-methoxyphenyl)pyrrolidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=374.1.

Example 123(6S,7S)—N-hydroxy-6-[(3-pyridin-4-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=345.2.

Example 124(6S,7S)—N-hydroxy-6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=384.2.

Example 125(6S,7S)—N-hydroxy-6-{[4-(3-trifluoromethoxyphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=440.1.

Example 126(6S,7S)—N-hydroxy-6-{[5-(methoxymethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=400.

Example 127(6S,7S)—N-hydroxy-6-(1,4,5,6-tetrahydrobenzo[f]isoquinolin-3(2H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=381.9.

Example 129(6S,7S)—N-hydroxy-6-{[4-(5-methoxy-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=400.2.

Example 130(6S,7S)—N-hydroxy-6-{[4-(4-methoxy-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=400.2.

Example 131(6S,7S)-6-[(4-cyano-4-phenylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=383.2.

Example 132 Ethyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M−H)−=426.1.

Example 133 Propyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M−H)−=440.2.

Example 134 Isopropyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M−H)−=440.2.

Example 135 Isobutyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M−H)−=454.2.

Example 136(6S,7S)—N-hydroxy-6-[(5-methyl-4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=370.

Example 143(6S,7S)-6-(1,4,4a,5,6,10b-hexahydrobenzo[f]isoquinolin-3(2H)-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=384.2.

Example 144(6S,7S)-6-{[4-(4-fluorophenyl)-3-hydroxypiperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=392.1.

Example 145(6S,7S)—N-hydroxy-6-(3,3a,8,8a-tetrahydroindeno[1,2-c]pyrrol-2(1H)-ylcarbonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=356.1.

Example 146(6S,7S)—N-hydroxy-6-{[4-(4-phenyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=441.3.

Example 147(6S,7S)—N-hydroxy-6-{[4-(4-tert-Butyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=421.1.

Example 148(6S,7S)—N-hydroxy-6-[(4-methyl-4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=372.2.

Example 149(6S,7S)—N-hydroxy-6-{[4-(4-ethyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=393.1.

Example 150(6S,7S)—N-hydroxy-6-{[(trans)-3-methyl-4-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.2.

Example 151(6S,7S)-6-{[4-(2-fluorophenyl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=377.2.

Example 152(6S,7S)-6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=398.1.

Example 153Tetrahydro-2H-pyran-4-yl-(6S,7S)-7-((hydroxyamino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate

Step 1. Preparation of tert-butyl(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylate

To a solution of(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid(160 mg, 0.63 mmole) in DMF (1.5 ml) was added 1-phenylpiperazine (112mg, 0.69 mmole), followed by addition of BOP (292 mg, 0.66 mmole). Afterstirring for 10 min, DIEA (204 mg, 1.57 mmole) was added. The mixturewas stirred at r.t. for 3 hours and quenched with sat. KH₂PO₄ solution,extracted with ethyl acetate. The extract was washed with water, brine,and dried over MgSO₄. After filtration, the filtrate was concentrated.The crude material was purified with flash column. tert-butyl(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylatewas obtained quantitativly. LC-MS: m/z 400.1 (M+H)+.

Step 2. Preparation of(6S,7S-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylicacid

The above product of tert-butyl(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylatewas stirred in 8 mL of 50% TFA in methylene chloride solution (v/v) for4 hours. After removal of solvent, the residue was dried under highvacuum overnight to give(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylicacid. LC-MS: m/z 344.1 (M+H)+.

Step 3. Preparation of(6S,7S)—N-(benzyloxy)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxamide

The above resulting material of(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylicacid (330 mg, 0.96 mmole) was dissolved in DMF (2 ml). To the resultingsolution, O-benzylhydroxylamine hydrochloride (307 mg, 1.92 mmole) wasadded, followed by BOP (510 mg, 1.15 mmole). After stirring 5 min, at 0°C., DIEA (437 mg, 3.36 mmole) was added. The mixture was stirred at r.tfor 3 hours and then quenched with sat KH₂PO₄ solution. The product wasextracted with ethyl acetate. The extract was washed with water, brine,and dried over MgSO₄. After filtration, the filtrate was concentrated toafford the desired product in quantitative yield.

Step 4.Tetrahydro-2H-pyran-4-yl(6S,7S)-7-(((benzyloxy)amino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate

(6S,7S)—N-(benzyloxy)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxamide(18.6 mg, 0.041 mmole) was mixed with 4-nitrophenyl-tetrahydropyran-4-ylcarbonate (13.3 mg, 0.050 mmole), and DIEA (11.0 mg, 0.083 mmole) in THFand stirred at r.t. for 24 hours. After concentration, the crudematerial was purified with flash column to afford the desired product(6.0 mg) in quantitative yield.

Step 5.Tetrahydro-2H-pyran-4-yl(6S,7S)-7-((hydroxyamino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate

Tetrahydro-2H-pyran-4-yl(6S,7S)-7-(((benzyloxy)amino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate(6.0 mg, 0.0104 mmole) was dissolved in methanol (0.3 ml) and 2 mg of 5%Pd/BaSO₄ was added to the resulting reaction mixture. The mixture wasstirred under hydrogen (1 atm) for 1.5 hours. After filtration, theproduct was purified with prep. RP-HPLC. The desired fractions werecollected and freeze dried to give 3.8 mg solid. LC-MS: m/z 487.1(M+H)+; 509.0 (M+Na)+.

Example 154 Ethyl(6S,7S)-7-((hydroxyamino)carbonyl))-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5-carboxylateStep 1. 7-tert-butyl-5-ethyl(6S,7S)-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5,7-dicarboxylate

The mixture of tert-butyl(6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylateprepared in example 153 (40 mg, 0.10 mmole), ethyl chloroformate (13 mg,0.12 mmole), and DIEA (26 mg, 0.2 mmole) in acetonitrile (0.20 ml) wasstirred at r.t. for 1 hour. After concentration, the residue waspurified with flash column. An amount of 29 mg of 7-tert-butyl-5-ethyl(6S,7S)-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5,7-dicarboxylatewas obtained. Yield: 61%. MS: m/z 472.3 (M+H)+.

Step 2.(6S,7S)-5-(ethoxycarbonyl))-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-7-dicarboxylicacid

The above material of 7-tert-butyl-5-ethyl(6S,7S)-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5,7-dicarboxylatewas stirred in 2 ml of 50% TFA in DCM solution (v/v) for 1.5 hours.After removal of solvent, the residue was dried under high vacuumovernight to quantitatively give the desired product. LC-MS: m/z 416.2(M+H)+; 853.4 (2M+Na)+.

Step 3. Ethyl(6S,7S)-7-((hydroxyamino)carbonyl))-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-5-carboxylate

To a solution of(6S,7S)-5-(ethoxycarbonyl))-6-((4-phenylpiperazin-1-yl)carbonyl-5-azaspiro(2,5)octane-7-dicarboxylicacid (30 mg, 0.072 mmole), hydroxylamine hydrochloride (15 mg, 0.217mmole), and BOP (34 mg, 0.076 mmole) in DMF (0.30 mL), DIEA (33 mg,0.253 mmole) was added. The mixture was stirred at r.t. for 2 hours. Thefinal product was purified with prep. HPLC to give a solid (14.5 mg)Yield: 37%. MS: m/z 431.2 (M+H)+; 883.5 (2 M+Na)+.

Example 155 Methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateStep 1 tert-Butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate

1-Phenylpiperazine (124 mg, 0.76 mmol) was added to a mixture of(6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid(180 mg, 0.70 mmol) and BOP (320 mg, 0.75 mmol) in DMF (4 mL) at 0° C.The mixture was stirred at 0° C. for 10 min, then N-methylmorpholine(300 μL) was added. The resulting mixture was stirred at RT forovernight, diluted with 5% NaHCO₃ and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with saturated brine anddried over Na₂SO₄. The solution was filtered and concentrated to afford248.4 mg of the tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate.

Step 2 7-tert-Butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate

Methyl chlorofomate (55 μL, 700 μL) was added to a solution oftert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate(248.4 mg, 0.62 mmol) and di-isopropylethylamine (0.70 mmol, 0.125 mL)in 5 mL acetonitrile. The mixture was stirred at RT for 3 h. Solvent wasremoved to afford a residue which was dissolved in ethyl ether (15 mL),washed with water (3×2 mL) and dried over Na₂SO₄. The solution wasfiltered and concentrated to afford 281 mg of the 7-tert-butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate.

Step 3 Methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

7-tert-Butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate(281 mg) was treated with a solution of 5 mL TFA in 5 mL ofdichloromethane and 1.0 mL of water. The mixture was stirred at RT forovernight. Solvents were removed under reduce pressure. The residue wasco-evaporated with methanol (2×3 mL), and dried under high vacuum.

The above residue was dissolved in DMF (4.0 mL) and cooled withice-water bath. To the resulting solution, PyBOP (320 mg) andhydroxylamine hydrochloride (125 mg) and N-methylmorpholine (320 μL)were added. After 15 min, the ice-water bath was removed and stirred atRT for 2 h. The mixture was adjusted to pH 2 with TFA. The resultingsolution was purified by HPLC to give 126 mg of desired product: methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate.MS(ESI): (M+H)+=417.1.

Example 156(6S,7S)—N-hydroxy-6-[(4-pyrazin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. MS(ESI): (M+H)+=361.2.

Example 157(6S,7S)—N-hydroxy-6-[(4-quinolin-2-ylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=410.1

Example 158(6S,7S)—N-hydroxy-6-{[3-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=398.2

Example 159(6S,7S)—N-hydroxy-5-methyl-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.1

Example 160 Methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=402.1.

Example 161(6S,7S)—N-hydroxy-6-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=345.1

Example 162(6S,7S)—N-hydroxy-6-[(3-pyridin-2-ylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=345.1

Example 163(6S,7S)—N-hydroxy-6-[(3-methyl-3-phenylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.2

Example 164(6S,7S)—N-hydroxy-6-[(3-phenylazetidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=330.3

Example 165(6S,7S)—N-hydroxy-5-methyl-6-[(3-methyl-3-phenylpyrrolidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=372.4

Example 166(6S,7S)—N-hydroxy-5-methyl-6-[(3-phenylazetidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=344.4

Example 168(6S,7S)-6-(1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindol-2-ylcarbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=370.4

Example 169(6S,7S)—N-hydroxy-6-{[3-(2-naphthyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=394.4

Example 170(6S,7S)—N-hydroxy-6-{[4-(2-thienyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=362.1

Example 171(6S,7S)—N-hydroxy-6-{[3-(3-thienyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=350.1

Example 172(6S,7S)—N-hydroxy-6-{[3-(2-thienyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=350.2

Example 173(6S,7S)—N-hydroxy-6-{[4-(2-thienyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=364.1

Example 174(6S,7S)—N-hydroxy-6-{[3-(2-methylphenyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.2

Example 175(6S,7S)—N-hydroxy-6-{[3-(4-methylphenyl)pyrrolidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.2

Example 176(6S,7S)-5-acetyl-N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M−H)+=396.2

Example 177(6S,7S)—N-hydroxy-6-{[4-(3-thienyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=362.1

Example 178(6S,7S)—N-hydroxy-6-[(3-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=358.2

Example 179(6S,7S)—N-hydroxy-6-{[4-(3-thienyl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=364.1

Example 180 Methyl(6S,7S)-6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=442.2

Example 181(6S,7S)-6-{[4-(3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=462.1

Example 182(6S,7S)-6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=392.2

Example 183(6S,7S)-6-{[4-(3,5-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=424.1

Example 184(6S,7S)-6-{[4-[3,5-bis(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=492.1

Example 185(6S,7S)—N-hydroxy-5-(methylsulfonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=437.2

Example 186(6S,7S)-5-formyl-N-hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=387.2

Example 187(6S,7S)-6-{[4-(3,5-difluorophenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=394.2

Example 188(6S,7S)-6-{[4-(2,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=384.1

Example 189(6S,7S)-6-{[4-(2,4,5-trimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=398.2

Example 190(6S,7S)-6-[(4-biphenyl-3-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=434.2

Example 191(6S,7S)-6-[(4-dibenzo[b,d]furan-4-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=448.2

Example 192(6S,7S)-6-{[4-(2,5-dimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=386.2

Example 193(6S,7S)-6-{[4-(2,4,5-trimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=400.2

Example 194 Methyl3-[1-({(6S,7S)-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-methylbenzoate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=428.2

Example 195(6S,7S)-6-[(5-phenyl-2,3,4,7-tetrahydro-1H-azepin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=370.2

Example 196(6S,7S)-6-{[4-[3-(dimethylamino)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=399.2

Example 197 Methyl3-[1-({(6S,7S)-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]oct-6-yl}carbonyl)piperidin-4-yl]-4-methylbenzoate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=430.2

Example 198(6S,7S)-6-[(5-phenylazepan-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=372.2

Example 199(6S,7S)-6-({4-[3-(dimethylamino)phenyl]piperidin-1-yl}carbonyl)-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=401.2

Example 200(6S,7S)-6-{[4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=370.2

Example 201(6S,7S)-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=342.1

Example 202(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=397.2

Example 203(6S,7S)-6-[(3,3-dimethyl-4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=384.1

Example 204(6S,7S)-6-[(3,3-dimethyl-4-phenylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=386.2.

Example 205(6S,7S)—N-hydroxy-5-(methylsulfonyl)-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)⁺=420.2

Example 206 Methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)⁺=400.2

Example 207(6S,7S)—N-hydroxy-5-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)⁺=356.2

Example 208(6S,7S)-6-{[4-(4-cyano-3-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. MS(ESI): (M+H)⁺=397.2

Example 209(6S,7S)-6-{[4-[3-(benzyloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMFwas added benzyl bromide (60 μL) at room temperature. The resultingmixture was stirred at 80° C. for 16 h. The mixture was cooled down,diluted with ethyl acetate, washed with water, brine, dried andconcentrated. The product (60 mg) was purified by combiflash usinghexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which wasthen converted to the final compound using procedures analogous to thosefor example 1. MS(ESI): (M+H)⁺=462.2

Example 210(6S,7S)-6-{[4-[3-ethylphenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=384.1

Example 211(6S,7S)-6-{[4-[3-(ethyloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=400.1

Example 212(6S,7S)-6-{[4-(3-ethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=386.1

Example 213(6S,7S)-6-{[4-(3-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=402.1

Example 214(6S,7S)-6-{[4-(3-cyclopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=396.2

Example 215(6S,7S)-6-{[4-(4-methoxy-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=414.2

Example 216(6S,7S)-6-{[4-(3,5-dimethyl-4-methoxyphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=416.2

Example 217(6S,7S)-6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamideStep 1. 4-Bromo-2-ethylbenzonitrile

To a solution of 4-bromo-2-methylbenzonitrile (0.4 g, 2.0 mmol) in dryTHF (10 mL) was slowly added LDA (1.3 mL, 1.8 M in THF) at −78° C. andstirred at this temperature for additional 30 min. Methyl iodide (0.15mL, 2.4 mmol) was added) at −78° C. to the above dark purple solutionand the mixture was warmed to room temperature over 3 h. The reactionwas quenched with water, extracted with ether, which was then was washedwith brine, dried and concentrated. 4-Bromo-2-ethylbenzonitrile (0.34 g)was purified by Combiflash.

Step 2. 2-ethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

4-Bromo-2-ethylbenzonitrile was converted to2-ethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile using thestandard Suzuki coupling.

Step 3. (6S,7S)-6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

Using procedures analogous to those of example 1,2-ethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile was converted tothe final compound(6S,7S)-6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide,MS(ESI): (M+H)⁺=409.2.

Example 218(6S,7S)-6-{[4-(4-cyano-3-ethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=411.2

Example 219(6S,7S)-6-{[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=409.2

Example 220(6S,7S)-6-{[4-(4-cyano-3,5-dimethylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=411.4

Example 221(6S,7S)-6-{[4-(1,3-benzothiazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

A solution of sodium nitrite (0.147 g, 2.1 mmol) in water (1.0 mL) wasslowly added to a suspension of 6-aminobenzothiazole (0.30 g, 2.0 mmol)in HBr (48% in water, 3 mL) at 0° C. and then the mixture was stirred atroom temperature for 30 min. The formed solution was then slowly addedto a solution of copper (I) bromide (0.435 g, 3.0 mmol) in HCl (conc., 5mL) at 0° C. After the addition, the mixture was stirred at 60° C. for1.5 h. Cooled down, and the reaction mixture was basified with excessammonia and extracted with diethyl ether. The combined extract waswashed with water, brine, dried and concentrated. The6-bromobenzothiazole (0.26 g) was obtained by Combiflash and thenconverted to the final compound using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=413.1.

Example 222(6S,7S)—N-hydroxy-6-{[4-(1-methyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamideStep 1. 5-bromo-2-methylphenyldiazonium tetrafluroborate

Sodium nitrite (0.56 g) in water (2.0 mL) was slowly added to a mixtureof 2-methyl-5-bromoaniline (1.50 g) in tetrafluoroboric acid (6.0 mL)and water (4.0 mL) at 0-5° C. After addition, the reaction was stirredat room temperature for 30 min. The mixture was cooled to 0° C.,filtered, washed with cold water, cold methanol and ether. The mixturewas then dried to provide the product 5-bromo-2-methylphenyldiazoniumtetrafluroborate (1.90 g).

Step 2. 6-bromoindazole

5-Bromo-2-methylphenyldiazonium tetrafluoroborate (1.50 g) was added toa mixture of potassium acetate (1.0 g) and 18-crown-6 (70 mg) inchloroform (50 mL) at room temperature in portions and then the reactionwas stirred for 2 h. The resulting mixture was filtered and washed withchloroform. The filtrate was concentrated, and the residue was dissolvedin diethyl ether, which was then washed with water, brine, dried, andthe solvent was removed to give the product 6-bromoindazole (0.9 g). Theproduct was used in the next step without further purification.

Step 3. 6-bromo-1-methylindazole

6-Bromoindazole (400 mg) was dissolved in methanol (10 mL). To thissolution, potassium hydroxide (450 mg) was added followed by methyliodide (0.50 mL) and the mixture was refluxed for 2.5 h. The reactionwas cooled, diluted with diethyl ether, washed with water, brine, driedand concentrated. The product 6-bromo-1-methylindazole (160 mg) wasseparated from its isomer by Combiflash.

Step 4.(6S,7S)—N-hydroxy-6-{[4-(1-methyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

6-Bromo-1-methylindazole was then converted into the final compoundusing proceudures similar to those described in example 1, MS(ESI):(M+H)⁺=410.2.

Example 223(6S,7S)—N-hydroxy-6-{[4-(1-methyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=412.3

Example 224(6S,7S)-6-{[4-(4-cyano-3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamideStep 1. 4-bromo-2-isopropylphenol

To a stirred solution of 2-isopropylphenol (2.0 g) in acetic acid (20mL) was added hydrobromic acid (48%, 10 mL) followed by dropwiseaddition of DMSO (10 mL). The mixture was stirred another 20 min anddiluted with water, extracted with diethyl ether. The combined extractwas washed with saturated NaHCO₃, water, brine, dried and concentratedto give the product 4-bromo-2-isopropylphenol (2.2 g, HPLC purity 95%).

Step 2. tert-butyl4-(4-hydroxy-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(0.36 g), 4-bromo-2-isopropylphenol (0.3 g) in DMF (8.0 mL) was addedpotassium carbonate (0.5 g) and PdCl₂dppf (60 mg) under nitrogen. Themixture was stirred at 80° C. for 16 h. The reaction was cooled down,diluted with ethyl acetate, washed with water, brine, dried andconcentrated. The product tert-butyl4-(4-hydroxy-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.12 g) was obtained by Combiflash.

Step 3. tert-butyl4-(3-isopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(4-hydroxy-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.10 g) in toluene (3.0 mL) at 0° C. was added triethyl amine (85 μL)followed by trifluoroacetic anhydride (60 μL). The reaction was warmedto room temperature and stirred for 2 h. The mixture was dumped tosaturated solution of NaHCO₃ and extracted with diethyl ether. Thecombined extract was washed with water, brine, dried and concentrated togive the product tert-butyl4-(3-isopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.14 g, 95% purity by HPLC).

Step 4. 2-isopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrilehydrochloride

A mixture of tert-butyl4-(3-isopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}-phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.14 g), zinc cyanide (65 mg), andtetrakis(triphenylphosphine)palladium(0) (25.0 mg) in DMF (3.0 mL) wasstirred at 100° C. under nitrogen for 4 h. The reaction was cooled down,diluted with water, extracted with diethyl ether. The combined extractwas washed with water, brine, dried and concentrated. tert-Butyl4-(4-cyano-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (85mg) was isolated by Combiflash. The isolated product was dissolved in aminimum amount of ethyl acetate and 4 N HCl in dioxane (3.0 mL) wasadded and stirred for 1 h. Diethyl ether (10 mL) was added and the solidwas filtered and washed with ether to give the product2-isopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride(65 mg).

Step 5.(6S,7S)-6-{[4-(4-cyano-3-isopropylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

2-Isopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloridewas then converted into the final compound using procedure similar tothose described in example 1, MS(ESI): (M+H)⁺=423.2

Example 225(6S,7S)-6-{[4-(4-cyano-3-isopropylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)+=425.2

Example 236(6S,7S)-6-{[4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=423.2

Example 237(6S,7S)-6-{[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-methyl-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=423.2

Example 238(6S,7S)—N-hydroxy-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. MS(ESI): (M+H)⁺=424.3

Example 239(6S,7S)—N-hydroxy-6-{[4-(1-methyl-1H-indazol-5-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=410.2

Example 240(6S,7S)—N-hydroxy-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)+=426.2

Example 241(6S,7S)—N-hydroxy-6-{[4-(1-methyl-1H-indazol-5-yl)piperidin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)+=412.2

Example 242(6S,7S)—N-hydroxy-6-{[4-(1-ethyl-1H-indazol-5-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=424.2

Example 243 Tetrahydro-2H-pyran-4-yl(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=554.3

Example 244 Methyl(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=482.2

Example 245(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=502.2

Example 246 Methyl(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=484.2

Example 247(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=504.2

Example 248(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=476.2

Example 249 Methyl(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=456.2

Example 250(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1, MS(ESI): (M+H)⁺=427.5

Example 251 Methyl(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=485.3

Example 252(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=505.2

Example 253 Tetrahydro-2H-pyran-4-yl(6S,7S)-6-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=526.3

Example 254 Tetrahydro-2H-pyran-4-yl(6S,7S)-6-{[4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154, MS(ESI): (M+H)⁺=455.3

Example 255(6S,7S)—N-hydroxy-6-[(3-methyl-4-phenylpiperidin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=372.1

Example 256(6S,7S)-6-{[5-(aminocarbonyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=386.1

Example 257(6S,7S)-6-{[4-(4-cyanophenyl)-5-methyl-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=395.2

Example 258(6S,7S)-6-{[4-(4-cyanophenyl)-3-methylpiperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=397.1

Example 259(6S,7S)—N-hydroxy-6-{[5-methyl-4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=415.2

Example 260(6S,7S)—N-hydroxy-6-{[5-methyl-4-(3-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=415.1

Example 262(6S,7S)-6-[(4-dibenzo[b,d]furan-2-yl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=446.1

Example 263(6S,7S)-6-[(4-dibenzo[b,d]furan-2-ylpiperidin-1-yl)carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=448.1

Example 264(6S,7S)-6-{[4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 31. Ms(ESI): (M+H)+=426.1

Example 265(6S,7S)-6-{[4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 86. Ms(ESI): (M+H)+=428.1

Example 266 Isopropyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 56. Ms(ESI): (M+H)+=428.1

Example 267 (3S)-tetrahydrofuran-3-yl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 56. Ms(ESI): (M+H)+=456.1

Example 268 Cyclohexyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 56. Ms(ESI): (M+H)+=468.2

Example 269 Tetrahydro-2H-pyran-4-yl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 56. Ms(ESI): (M+H)+=470.2

Example 270(5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxamide Step 1. Preparation of(1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid

tert-Butyl (1 S,2S,5S)-7-oxo-6-oxabicyclo(3,2,1)octane-2-carboxylate wasdissolved in THF-H₂O. At 0° C., LiOH (3 eq.) was added and the resultingmixture was stirred at 0° C. for 2 hours. TLC showed starting materialwas consumed. The mixture was then acidified to pH of about 2. Theproduct was extracted with EtOAc (×3). The combined extracts were washedwith brine (×1); dried over MgSO₄. After filtration, the filtrate wasconcentrated to give(1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid(quantitative).

Step 2. Preparation of2-Benzyl-1-tert-butyl(1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate

(1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid(1.07 g, 4.38 mmole) was dissolved in benzene (20 ml). To the solution,benzyl bromide was added ar r.t., followed by DBU. The mixture wasstirred at r.t. for 3 hours. The resulting mixture was quenched with 1NHCl solution and extracted with EtOAc (×2). The combined extracts werewashed with 10% citric acid (×1); brine (×1); and dried over MgSO₄.After filtration, the filtrate was concentrated to afford2-Benzyl-1-tert-butyl(1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate.

Step 3. Preparation of2-Benzyl-1-tert-butyl(1S,2S)-4-oxocyclohexane-1,2-dicarboxylate

(1S,2S,4S)-1-tert-butyl 2-benzyl 4-hydroxycyclohexane-1,2-dicarboxylate(1.47 g, 4.40 mmole) was dissolved in DCM (30 ml). Dess-Martin reagentwas added at r.t. to the solution with stirring. After 2 hours, TLCshowed starting material was consumed. The mixture was quenched withsat'd Na₂S₂O₃ solution and then extracted with EtOAc (×2). The combinedextracts were washed with water (×1), brine (×1); and dried over MgSO₄.After filtration, the filtrate was concentrated. The resulting residuewas purified with combi-flash and eluted with EtOAc/Hexane to give2-Benzyl-1-tert-butyl(1S,2S)-4-oxocyclohexane-1,2-dicarboxylate.

Step 5. Preparation of2-Benzyl-1-tert-butyl(1S,2S)-4-methylenecyclohexane-1,2-dicarboxylate

Methyl triphenylphosphonium bromide (1.9 g, 5.32 mmole) and sodiumbis(trimethylsilyl)amide (1.0 M in THF, 5.32 ml, 5.32 mmole) in toluene(15 ml)/THF (5 mL) solution was combined with a solution of(1S,2S)-1-tert-butyl 2-benzyl 4-oxocyclohexane-1,2-dicarboxylate (1.0 g,4.09 mmole) in toluene (15 mL) at −10° C. The resulting mixture wasstirred at r.t. for 2 hours at −10° C. and at r.t for 2 hours. TLCshowed starting material was consumed. The mixture was diluted withEtOAc, and the resulting solution was washed with water (×1); brine(×2); and dried over MgSO₄. After filtration, the filtrate wasconcentrated. The crude product was purified with combi-flash to afford(1S,2S)-1-tert-butyl 2-benzyl 4-methylenecyclohexane-1,2-dicarboxylate(0.65 g; 1.97 mmole).

Step 6. Preparation of 5-Benzyl-6-tert-butyl(5S,6S)-spiro(2,5)octane-5,6-dicarboxylate

To a solution of KOH (1.9 g) in water (3 ml), di(ethylene glycol) ethylether (9 ml), and ethyl ether (10 ml) in flask A, 1.0 g of diazald wasadded in three portions. After addition of the first portion, the flaskwas put into a pre-heated (at 60° C.) oil bath in order to distill outCH₂N₂ which was transferred to flask B pre-chilled to around −15° C. andcontaining the compound (1S,2S)-1-tert-butyl 2-benzyl4-methylenecyclohexane-1,2-dicarboxylate (200 mg), and Pd(OAc)₂ (80 mg)in ether (10 ml). After 5 minutes, the oil bath was removed from flaskA. Then, the second portion of diazald was added, and the aboveprocedure was repeated twice. After completion of the distillation ofCH₂N₂ with ether into flask B, the cold bath was removed from Flask B.The reaction mixture was stirred at r.t. for 2 hours, then filteredthrough silica gel and rinsed with ethyl acetate and methylenechloride.The filtrate was concentrated. The resulting residue is the desiredproduct 5-Benzyl-6-tert-butyl(5S,6S)-spiro(2,5)octane-5,6-dicarboxylate, confirmed by ¹H NMR. Theproduct was directly used in next step reaction without furtherpurification.

Step 7. Preparation of(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid

The product of the previous step 6 was stirred in DCM/TFA (1:1)overnight and then concentrated to yield(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid.

Step 8. Preparation of Benzyl(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylate

(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid fromstep 7 (47 mg, 0.16 mmole) was dissolved in DMF (0.7 mL). To thesolution, 1-phenylpiperazine (29 mg, 0.18 mmole) was added, followed byBOP (76 mg, 0.17 mmole). DIEA (53 mg, 0.41 mmole) was added after themixture was stirred at r.t. for 10 min. The mixture was then stirred atr.t. overnight and quenched with sat'd NaHCO₃ solution, extracted withEtOAc. The extract was washed with NaHCO₃ sat'd solution, brine; driedover MgSO₄. After filtration, the filtrate was concentrated. Theresulting residue was purified by column chromatography to afford Benzyl(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylate.

Step 9. Preparation of(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylic acid

The product of the previous step 8 was dissolved in methanol. To thesolution, 5% Pd—BaSO₄ was added. The mixture was stirred under ahydrogen atmosphere at r.t. for 2 hours. After removal of solid, thesolution was concentrated to dryness (yield: 30%) to give(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylic acid.

Step 10. Preparation of(5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxamide

The product from step 9 (36 mg, 0.105 mmole), and hydroxylaminehydrochloride (22 mg, 0.315 mmole) were dissolved in DMF (0.70 ml). Tothe solution, BOP (49 mg, 0.11 mmole) was added with stirring at r.t.for 10 min. DIEA (61 mg, 0.47 mmole) was added. The mixture was stirredat r.t. for 2 hours. The product was purified with preparative HPLCproviding 22 mg of(5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxamide. Yield: 44%. MS: M/Z 358.2 (M+H)+; 380.2 (M+Na)+;737.2 (2M+Na)+.

Example 271(6S)—N-hydroxy-6-{[(3R)-3-phenylpyrrolidin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous to those of thepreparation of example 270. MS:M/Z 343.3 (M+H)+; 365.2 (M+Na)+; 707.3(2M+Na)+.

Example 272(5S,6S)—N-hydroxy-6-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous to those of thepreparation of example 270. MS:M/Z 417.2 (M+H)+.

Example 273(5S,6S)—N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide

This compound was prepared using procedures analogous those for thepreparation of example 270. MS: M/Z 355.2 (M+H)+; 377.2 (M+Na)+; 731.4(2M+Na)+.

Example 274 (3S)-tetrahydrofuran-3-yl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogues to the example154. MS: m/z 473.2 (M+H)+; 495.0 (M+Na)+.

Example 275 (3R)-tetrahydrofuran-3-yl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogues to the example154. MS: m/z 473.2 (M+H)+; 495.2 (M+Na)+.

Example 276 2-Methoxyethyl(6S,7S)-7-((hydroxyamino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate

This compound was prepared using procedures analogues to the example154. MS: m/z 461.1 (M+H)+; 483.1 (M+Na)+.

Example 277(6S,7S)—N-hydroxy-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogues to the example154. MS: m/z 499.1 (M+H)+.

Example 278 Propyl(6S,7S)-7-[(hydroxyamino)carbonyl)]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2,5]octane-5-carboxylate

This compound was prepared using procedures analogues to the example154. MS: m/z 445.2 (M+H)+.

Example 279 Isopropyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogues to the example154. MS: m/z 445.2 (M+H)+; 467.2 (M+Na)+.

Example 280 Methyl(6S,7S)-6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=450.2.

Example 281 Methyl(6S,7S)-6-{[4-(3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl}-7-[(hydroxyamino)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=470.2

Example 282(6S,7S)—N-hydroxy-6-{[4-(4-isopropylphenyl)piperazin-1-yl]carbonyl}-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=400.2

Example 283(6S,7S)-6-{[4-(3,5-difluorophenyl)piperidin-1-yl]carbonyl}-N-hydroxy-5-(methylsulfonyl)-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 154. Ms(ESI): (M+H)+=472.1

Example 284(6S,7S)-6-{[4-(4,5-dimethyl-1,3-thiazol-2-yl)piperidin-1-yl]carbonyl}-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide

This compound was prepared using procedures analogous to those forexample 1. Ms(ESI): (M+H)+=393.1.

Compounds of the Examples are listed below in Table 1.

TABLE 1

MS: Exp. Core NR″R′′′ R′ M + H 1 A 4-(3-methylphenyl)piperazin-1-y1 Me387.1 2 A 4-phenylpiperazin-1-y1 Me 373.2 3 A4-[3-(trifluoromethyl)phenyl]piperazin-1-y1 Me 441 4 A4-(2-methylphenyl)piperazin-1-y1 Me 387.1 5 A4-(4-Chlorophenyl)piperazin-1-y1 Me 407.1 6 A4-(2-methyl-4-nitrophenyl)piperazin-l-yl Me 432 7 A4-phenylpiperidin-1-y1 Me 372.2 8 A 4-hydroxy-4-phenylpiperidin-1-y1 Me388 9 A 4-phenyl-3,6-dihydropyridin-1(2H)-y1 Me 370 11 A4-quionolin-2-ylpiperazin-1-yl Me 424.3 12 A4-(2,3-dichlorophenyl)piperazin-1-yl Me 441 13 A4-quinolin-4-ylpiperazin-1-yl Me 424.3 14 A4-(2-methylquinolin-4-yl)piperazin-1-yl Me 438.4 15 A4-(2-phenylethyl)piperazin-1-yl Me 401.3 16 A4-pyridin-4-ylpiperidin-1-yl Me 373.3 17 A4-(4-nitrophenyl)piperazin-1-yl Me 418.3 18 A4-(2-methoxyphenyl)piperazin-1-yl Me 403 19 A 4-phenoxypiperidin-1-yl Me388.3 20 A 3,4-dihydroisoquinolin-2(1H)-yl Me 344.3 21 A4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl Me 350.2 22 A3-benzylpyrrolidin-1-yl Me 372.3 23 A 4-pyridin-2-ylpiperazin-1-yl Me374.2 24 A 4-(2-pyridin-4-ylethyl)piperidin-1-yl Me 401.3 25 A4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl Me 442.3 26 A4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl Me 442.3 27 A1,4′-bipiperidin-1′-yl Me 379.3 28 A4-(pyridin-2-ylmethyl)piperazin-1-yl Me 388.3 29 A4-(pyridin-4-ylmethyl)piperazin-1-yl Me 388.3 30 A4-(pyridin-3-ylmethyl)piperazin-1-yl Me 388.3 31 A4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl Me 384.1 32 A4-(3-methylphenyl)piperazin-1-yl H 373.1 33 A1,3,4,9-tetrahydro-2H-β-carbolin-2-yl Me 383 34 A9-methyl-1,3,4,9-tetrahydro-2H-β-carbolin-2-yl Me 396.9 35 A4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl Me 388 36 A4-(2-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl Me 404 37 A4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl Me 415.1 38 A4-phenyl-3,6-dihydropyridin-1(2H)-yl H 356 39 A4-(2-methyl-4-nitrophenyl)piperazin-1-yl H 418 40 AN-methyl-N′-(3-phenylpropyl)amino Me 360.1 41 A isobutylamino Me 284 42A 4-(2-nitrophenyl)piperazin-1-yl Me 418 43 AN-methyl-N′-(isobutyl)amino Me 298 44 A (2-phenoxyethyl)-amino Me 348 45A 2-(4-methoxyphenyl)ethylamino Me 362 46 A 4-phenylbutylamino Me 360 47A 3-(2-oxopyrrolidin-1-yl)propylamino Me 353 48 A3,4,10,10a-tetrahydropyrazino[1,2-a]indol- H 385 2(1H)-yl 49 D4-(2-methyl-4-nitrophenyl)piperazin-1-yl 417.2 50 B4-(3-methylphenyl)piperazin-1-yl 372.2 51 D4-phenyl-3,6-dihydropyridin-1(2H)-yl 355 52 D4-(3-methylphenyl)piperazin-1-yl 372 53 B4-phenyl-3,6-dihydropyridin-1(2H)-yl 355 54 A3,4,10,10a-tetrahydropyrazino[1,2-a]indol- H 371.2 2(1H)-yl 55 A1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2- Me 399.4 a]quinolin-3-yl 56 A4-phenyl-3,6-dihydropyridin-1(2H)-yl methoxycarbonyl 414 57 A4-phenyl-3,6-dihydropyridin-1(2H)-y1 benzyloxycarbonyl 490 58 A4-pheny1-3,6-dihydropyridin-1(2H)-y1 methylsulfonyl 434 59 A3-(3-methoxyphenyl)piperidin-1-yl Me 402.4 60 A3-(2-phenylethyl)pyrrolidin-1-yl Me 386 61 A4-(3-methoxyphenyl)piperidin-1-yl Me 402.4 62 A4-[3-(aminocarbonyl)phenyl]-3,6- H 398.9 dihydropyridin-1(2H)-yl 63 A4-(2-methoxyphenyl)piperidin-1-yl Me 402.4 64 A4-(3fFluoro-2-methylphenyl)piperazin-l-y1 H 391.3 65 A4-(2-methyl-3-nitrophenyl)piperazin-l-yl H 418.3 66 A3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl H 357.4 67 AN-(4-methoxypheny1)-N′-methylamino H 334 68 A4-(3-methoxyphenyl)piperazin-1-y1 Me 403 69 A4-(3-Chlorophenyl)piperazin-1 -y1 Me 407.3 70 A4-Phenyl-[1,4]diazepan-1-y1 H 373 71 A3-methyl-4-(3-methylphenyl)piperazin-1-yl H 387 72 A4-(3-methoxyphenyl)piperidin-1-yl H 388.4 73 B 3-phenylpyrrolidin-1-y1343.3 74 A 4-isobutyrylpiperazin-1-y1 H 353 75 A4-(4-cyano-2-methyphenyl)-3,6-dihydropyridin- H 395 1(2H)-yl 76 A4-[(2-methylquinolin-4-yl)methoxy]phenylamino Me 475.4 77 A4-[(2-methylquinolin-4-yl)methoxy]phenylamino H 461 78 A4-(4-cyanophenyl)piperazin-1-y1 H 384 79 C 4-phenylpiperidin-1-y1 H 35880 A 4-phenylpiperidin-1-yl H 358 81 A 4-phenylpiperazin-1-yl H 359 82 A4-[3-(methoxymethyl)phenyl]piperidin-1-yl H 402 83 A4-(3-methoxycarbonylphenyl)piperidin-1-yl H 416 84 A3-cyclohexylpyrrolidin-1-yl H 350.4 85 A4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)- H 398.4 yl 86 A4-(3-Isopropylphenyl)piperidin-1-y1 H 400.4 87 A4-(4-propylphenyl)-3,6-dihydropyridin-1(2H)-yl H 398 88 A4-(4-ethylphenyl)-3,6-dihydropyridin-1(2H)-yl H 384.4 89 A4-(4-ethylphenyl)piperidin-1-yl H 386 90 A4-(4-cyano-2-methylphenyl)piperazin-1-yl H 398 91 A4-(3-isopropoxyphenyl)-3,6-dihydropyridin- H 414.4 1(2H)-yl 92 A4-(3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl H 370.3 93 A4-(3-methylphenyl)piperazin-1-yl H 372.4 94 A4-(4-tert-butylphenyl)piperazin-1-yl H 415.4 95 A4-pyridin-4-ylpiperazin-1-yl H 360 96 A 3-benzylpiperidin-1-yl H 371.997 A 5-methoxy-2,3-dihydro-1H-indol-1-yl H 346.3 98 A5-[(2-methylquinolin-4-yl)methoxy]-2,3- H 487.4 dihydro-1H-indol-1-yl 99A 5-[(2-methylquinolin-4-yl)methoxy]-2,3- Me 501.4 dihydro-1H-indol-1-yl100 A 5-(benzyloxy)-2,3-dihydro-1H-indol-1-yl H 422.3 101 A1,3-dihydro-1′H-spiro[indene-2,4′-piperidin]-1′- H 384.4 yl 102 A4-(3-isopropoxyphenyl)piperidin-1-yl H 416.4 103 A4-(2-methyl-4-methoxycarbonylphenyl)-3,6- H 427.9dihydropyridin-1(2H)-yl 104 A4-(2-methyl-4-nitrophenyl)-3,6-dihydropyridin- H 414.8 1(2H)-yl 105 A4-(2-ethylphenyl)piperidin-1-yl H 385.9 106 A 4-(2-methyl-4- H 429.9methoxycarbonylphenyl)piperidin-1-yl 107 A4-(2,3-dihydro-1-benzofuran-5-yl)-3,6- Me 412.2 dihydropyridin-1(2H)-yl108 A 4-(3-isopropylphenyl)-3,6-dihydropyridin-1(2H)- Me 412.2 yl 109 A(3R)-3-phenylpyrrolidin-1-yl H 344.1 110 A (3S)-3-phenylpyrrolidin-1-ylH 344.1 112 A 3-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl H 412.1 113 A3-(3-chlorophenyl)pyrrolidin-1-yl H 378.1 114 A3-(3-fluorophenyl)pyrrolidin-1-yl H 362.1 115 A3-(4-fluorophenyl)pyrrolidin-1-yl H 362.1 116 A3-(4-chlorophenyl)pyrrolidin-1-yl H 378.1 117 A3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl H 412.1 118 A3-(4-methoxyphenyl)pyrrolidin-1-yl H 374.1 119 A3-(4-phenoxyphenyl)pyrrolidin-1-yl H 436.2 120 A4-(3-methoxyphenyl)-3,6-dihydropyridin-1(2H)- H 386.1 yl 121 A4-(4-cyano-3-methylphenyl)-3,6-dihydropyridin- H 395.1 1(2H)-yl 122 A3-(3-methoxyphenyl)pyrrolidin-1-yl H 374.1 123 A3-pyridin-4-ylpyrrolidin-1-yl H 345.2 124 A4-(3,5-dimethylphenyl)-3,6-dihydropyridin- H 384.2 1(2H)-yl 125 A4-(3-trifluoromethoxyphenyl)-3,6- H 440.1 dihydropyridin-1(2H)-yl 126 A5-(methoxymethyl)-4-phenyl-3,6- H 400 dihydropyridin-1(2H)-yl 127 A1,4,5,6-tetrahydrobenzo[f]isoquinolin-3(2H)-yl H 381.9 129 A4-(5-methoxy-2-methylphenyl)-3,6- H 400.2 dihydropyridin-1(2H)-yl 130 A4-(4-methoxy-2-methylphenyl)-3,6- H 400.2 dihydropyridin-1(2H)-yl 131 A4-cyano-4-phenylpiperidin-1-yl H 383.2 132 A4-phenyl-3,6-dihydropyridin-1(2H)-yl Ethoxycarbonyl 426.1* 133 A4-phenyl-3,6-dihydropyridin-1(2H)-yl Propionoxycarbonyl 440.2* 134 A4-phenyl-3,6-dihydropyridin-1(2H)-yl iso- 440.2* propionoxycarbonyl 135A 4-phenyl-3,6-dihydropyridin-1(2H)-yl isobutoxycarbonyl 454.2* 136 A5-methyl-4-phenyl-3,6-dihydropyridin-1(2H)-yl H 370 143 A1,4,4a,5,6,10b-hexahydrobenzo[f]isoquinolin- H 384.2 3(2H)-yl 144 A4-(4-fluorophenyl)-3-hydroxypiperidin-1-yl H 392.1 145 A3,3a,8,8a-tetrahydroindeno[1,2-c]pyrrol-2(1H)-yl H 356.1 146 A4-(4-phenyl-1,3-thiazol-2-yl)piperidin-1-yl H 441.3 147 A4-(4-tert-Butyl-1,3-thiazol-2-yl)piperidin-1-yl H 421.1 148 A4-methyl-4-phenylpiperidin-1-yl H 372.2 149 A4-(4-ethyl-1,3-thiazol-2-yl)piperidin-1-yl H 393.1 150 A3-methyl-4-phenylpyrrolidine-1-yl H 358.2 151 A4-(2-fluorophenyl)piperazin-1-yl H 377.2 152 A4-(3,5-dimethylphenyl)-3,6-dihydropyridin- Me 398.1 1(2H)-yl 153 A4-phenylpiperazin-1-yl tetrahydro-2H-pyran- 487.1 4-oxycarbonyl 154 A4-phenylpiperazin-1-yl ethoxycarbonyl 431.2 155 A 4-phenylpiperazin-1-ylmethoxycarbonyl 417.1 156 A 4-pyrazin-2-ylpiperazin-1-yl H 361.2 157 A4-quinolin-2-ylpiperazin-1-yl H 410.1 158 A3-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin- H 398.2 1-yl 159 A(3R)-3-phenylpyrrolidin-1-yl Me 358.1 160 A (3R)-3-phenylpyrrolidin-1-ylmethoxycarbonyl 402.1 161 A 3-pyridin-3-ylpyrrolidin-1-yl H 345.1 162 A3-pyridin-2-ylpyrrolidin-1-yl H 345.1 163 A3-methyl-3-phenylpyrrolidine-1-yl H 358.2 164 A 3-phenylazetidin-1-yl H330.3 165 A 3-methyl-3-phenylpyrrolidine-1-yl Me 372.4 166 A3-phenylazetidin-1-yl Me 344.4 168 A1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindol-2- H 370.4 yl 169 A3-(2-naphthyl)pyrrolidin-1-yl H 394.4 170 A4-(2-thienyl)-3,6-dihydropyridin-1(2H)-yl H 362.1 171 A3-(3-thienyl)pyrrolidin-1-yl H 350.1 172 A 3-(2-thienyl)pyrrolidin-1-ylH 350.2 173 A 4-(2-thienyl)piperidin-1-yl H 364.1 174 A3-(2-methylphenyl)pyrrolidin-1-yl H 358.2 175 A3-(4-methylphenyl)pyrrolidin-1-yl H 358.2 176 A4-phenyl-3,6-dihydropyridin-1(2H)-yl Ac 396.2 177 A4-(3-thienyl)-3,6-dihydropyridin-1(2H)-yl H 362.1 178 A3-phenylpiperidin-1-yl H 358.2 179 A 4-(3-thienyl)piperidin-1-yl H 364.1180 A 4-(3,5-dimethylphenyl)-3,6-dihydropyridin- methoxycarbonyl 442.21(2H)-yl 181 A 4-(3,5-dimethylphenyl)-3,6-dihydropyridin-methanesulfonyl 462.1 1(2H)-yl 182 A4-(3,5-difluorophenyl)-3,6-dihydropyridin- H 392.2 1(2H)-yl 183 A4-(3,5-dichlorophenyl)-3,6-dihydropyridin- H 424.1 1(2H)-yl 184 A4-[3,5-bis(trifluoromethyl)phenyl]-3,6- H 492.1 dihydropyridin-1(2H)-yl185 A 4-phenylpiperazin-1-yl methanesulfonyl 437.2 186 A4-phenylpiperazin-1-yl formyl 387.2 187 A4-(3,5-difluorophenyl)piperidin-1-yl H 394.2 188 A4-(2,5-dimethylphenyl)-3,6-dihydropyridin- H 384.1 1(2H)-yl 189 A4-(2,4,5-trimethylphenyl)-3,6-dihydropyridin- H 398.2 1(2H)-yl 190 A4-biphenyl-3-ylpiperidin-1-yl H 434.2 191 A4-dibenzo[b,d]furan-4-yl)piperidin-1-yl H 448.2 192 A4-(2,5-dimethylphenyl)piperidin-1-yl H 386.2 193 A4-(2,4,5-trimethylphenyl)piperidin-1-yl H 400.2 194 A4-(3-methoxycarbonyl)-6-methylphenyl)-3,6- H 428.2dihydropyridin-1(2H)-yl 195 A 5-phenyl-2,3,4,7-tetrahydro-1H-azepin-1-ylH 370.2 196 A 4-[3-(dimethylamino)phenyl]-3,6- H 399.2dihydropyridin-1(2H)-yl 197 A 4-(3-methoxycarbonyl-6- H 430.2methylphenyl)piperidin-1-yl 198 A 5-phenylazepan-1-yl H 372.2 199 A4-[3-(dimethylamino)phenyl]piperidin-1-yl H 401.2 200 A4-(2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl H 370.2 201 A3-phenyl-2,5-dihydro-1H-pyrrol-1-yl H 342.1 202 A4-(4-cyano-2-methylphenyl)piperidin-1-yl H 397.2 203 A3,3-dimethyl-4-phenyl-3,6-dihydropyridin- H 384.1 1(2H)-yl 204 A3,3-dimethyl-4-phenylpiperidin-1-yl H 386.2 205 A3-phenyl-2,5-dihydro-1H-pyrrol-1-yl methanesulfonyl 420.2 206 A3-phenyl-2,5-dihydro-1H-pyrrol-1-yl methoxycarbonyl 400.2 207 A3-phenyl-2,5-dihydro-1H-pyrrol-1-yl Me 356.2 208 A4-(4-cyano-3-methylphenyl)piperidin-1-yl H 397.2 209 A4-[3-(benzyloxy)phenyl]-3,6-dihydropyridin- H 462.2 1(2H)-yl 210 A4-[3-ethylphenyl]-3,6-dihydropyridin-1(2H)-yl H 384.1 211 A4-[3-(ethyloxy)phenyl]-3,6-dihydropyridin- H 400.1 1(2H)-yl 212 A4-(3-ethylphenyl)piperidin-1-yl H 386.1 213 A4-(3-ethoxyphenyl)piperidin-1-yl H 402.1 214 A4-(3-cyclopropylphenyl)-3,6-dihydropyridin- H 396.2 1(2H)-yl 215 A4-(4-methoxy-3,5-dimethylphenyl)-3,6- H 414.2 dihydropyridin-1(2H)-yl216 A 4-(3,5-dimethyl-4-methoxyphenyl)piperidin-1-yl H 416.2 217 A4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin- H 409.2 1(2H)-yl 218 A4-(4-cyano-3-ethylphenyl)piperidin-1-yl H 411.2 219 A4-(4-cyano-3,5-dimethylphenyl)-3,6- H 409.2 dihydropyridin-1(2H)-yl 220A 4-(4-cyano-3,5-dimethylphenyl)piperidin-1-yl H 411.4 221 A4-(1,3-benzothiazol-6-yl)-3,6-dihydropyridin- H 413.1 1(2H)-yl 222 A4-(1-methyl-1H-benzimidazol-6-yl)-3,6- H 410.2 dihydropyridin-1(2H)-yl223 A 4-(1-methyl-1H-benzimidazol-6-yl)piperidin-1-yl H 412.3 224 A4-(4-cyano-3-isopropylphenyl)-3,6- H 423.2 dihydroypridin-1(2H)-yl 225 A4-(4-cayno-3-isopropylphenyl)piperidin-1-yl H 425.2 236 A4-(4-cyano-3-ethylphenyl)-3,6-dihydropyridin- Me 423.2 1(2H)-yl 237 A4-(4-cyano-3,5-dimethylphenyl)-3,6- Me 423.2 dihydropyridin-1(2H)-yl 238A 4-(1-ethyl-1H-benzimidazol-6-yl)-3,6- H 424.3 dihydropyridin-1(2H)-yl239 A 4-(1-methyl-1H-indazol-5-yl)-3,6- H 410.2 dihydropyridin-1(2H)-yl240 A 4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl H 426.2 241 A4-(1-methyl-1H-indazol-5-yl)piperidin-1-yl H 412.2 242 A4-(1-ethyl-1H-indazol-5-yl)-3,6-dihydropyridin- H 424.2 1(2H)-yl 243 A4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl tetrahydro-2H-pyran-554.3 4-oxycarbonyl 244 A 4-(1-ethyl-1H-benzimidazol-6-yl)-3,6-methoxycarbonyl 482.2 dihydropyridin-1(2H)-yl 245 A4-(1-ethyl-1H-benzimidaozl-6-yl)-3,6- methanesulfonyl 502.2dihydropyridin-1(2H)-yl 246 A4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl methoxycarbonyl 484.2 247A 4-(1-ethyl-1H-benzimidazol-6-yl)piperidin-1-yl methanesulfonyl 504.2248 A 4-(4-cyano-2-methylphenyl)piperidin-1-yl methanesulfonyl 476.2 249A 4-(4-cyano-2-methylphenyl)piperazin-1-yl methoxycarbonyl 456.2 250 A4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl H 427.5 251 A4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl methoxycarbonyl 485.3 252A 4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yl methanesulfonyl 505.2253 A 4-(4-cyano-2-methylphenyl)piperazin-1-yl tetrahydro-2H-pyran-526.3 4-oxycarbonyl 254 A 4-(1-ethyl-1H-benzimidazol-6-yl)piperazin-1-yltetrahydro-2H-pyran- 455.3 4-oxycarbonyl 255 A3-methyl-4-phenylpiperidin-1-yl H 372.1 256 A5-(aminocarbonyl)-4-phenyl-3,6-dihydropyridin- H 386.1 1(2H)-yl 257 A4-(4-cyanophenyl)-5-methyl-3,6-dihydropyridin- H 395.2 1(2H)-yl 258 A4-(4-cyanophenyl)-3-methylpiperidin-1-yl H 397.1 259 A5-methyl-4-(4-nitrophenyl)-3,6-dihydropyridin- H 415.2 1(2H)-yl 260 A5-methyl-4-(3-nitrophenyl)-3,6-dihydropyridin- H 415.1 1(2H)-yl 262 A4-dibenzo[b,d]furan-2-yl-3,6-dihydropyridin- H 446.1 1(2H)-yl 263 A4-dibenzo[b,d]furan-2-ylpiperidin-1-yl H 448.1 264 A4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- H 426.13,6-dihydropyridin-1(2H)-yl 265 A4-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5- H 428.1 yl)piperidin-1-yl266 A 3-phenyl-2,5-dihydro-1H-pyrrol-1-yl iso- 428.1 propionoxycarbonyl267 A 3-phenyl-2,5-dihydro-1H-pyrrol-1-yl (3S)-tetrahydrofuran- 456.13-oxycarbonyl 268 A 3-phenyl-2,5-dihydro-1H-pyrrol-1-ylcyclohexoxycarbonyl 468.2 269 A 3-phenyl-2,5-dihydro-1H-pyrrol-1-yltetrahydro-2H-pyran- 470.2 4-oxycarbonyl 270 B 4-phenylpiperazin-1-yl358.2 271 B (3R)-3-phenylpyrrolidin-1-yl 343.3 272 B4-(2-methyl-4-nitrophenyl)piperazin-1-yl 417.2 273 B4-phenyl-3,6-dihydropyridin-1(2H)-yl 355.2 274 A 4-phenylpiperazin-1-yl(3S)-tetrahydrofuran- 473.2 3-oxycarbonyl 275 A 4-phenylpiperazin-1-yl(3R)- 473.2 tetrahydrofuran-3- oxycarbonyl 276 A 4-phenylpiperazin-1-yl2- 461.1 methoxyethoxy- carbonyl 277 A 4-phenylpiperazin-1-ylphenylsulfonyl 499.1 278 A 4-phenylpiperazin-1-yl propionoxycarbonyl445.2 279 A 4-phenylpiperazin-1-yl iso- 445.2 propionoxycarbonyl 280 A4-(3,5-difluorophenyl)-3,6-dihydropyridin- methoxycarbonyl 450.21(2H)-yl 281 A 4-(3,5-difluorophenyl)-3,6-dihydropyridin-methanesulfonyl 470.2 1(2H)-yl 282 A 4-(4-isopropylphenyl)piperazin-1-ylH 400.2 283 A 4-(3,5-difluorophenyl)piperidin-1-yl methanesulfonyl 472.1284 A 4-(4,5-dimethyl-1,3-thiazol-2-yl)piperidin-1-yl H 393.1 *M − H

The capacity of the novel compounds of the invention to inhibitmetalloproteases can be determined using a suitable screen such as ahigh through-put assay. For example, an agent can be tested in anextracellular acidification assay, calcium flux assay, ligand bindingassay or chemotaxis assay. Below are example assays.

TNFα Assay

In some embodiments, the capacity of the compounds of the invention toact as inhibitors of the production of TNFα can be determined using thefollowing procedure. A 100 μM solution of the inhibitor being tested ordilutions thereof is incubated at 37° C. in an atmosphere of 5% CO₂ withTHP-1 cells (human monocytes) suspended in RPM1 1640 medium and 20 μMβ-mercaptoethanol at a cell density of 1×10⁶/ml and stimulated with LPS.After 18 hours the supernatant is assayed for the levels of TNFα using acommercially available ELISA kit. The activity in the presence of 0.1 mMinhibitor or dilutions thereof is compared to activity in a controldevoid of inhibitor and results reported as that inhibitor concentrationeffecting 50% inhibition of the production of TNFα.

PBMC Assay Measuring TNFα Activity

A leukophoresis is obtained from (Biological Specialties, Colmar Pa.)from normal drug free (no aspirin, ibuprofen, NSAIDs) etc.) donors. In a50 mL conical tube (VWR, NJ), add 20 mL of blood and 20 mL of sterile0.9% saline (Baxter Healthcare, Dearfield, Ill.) and mix well. Underlay10 mL of endotoxin free ficoll paque (Pharmacia, Uppsala, Sweden) andspin at 3000 RPM for 30 minutes. Remove the layer of white blood cellsand wash with 50 mls 0.9% saline. Count cells and add 0.250 mL to 96well plate (Costar/Corning VWR, NJ) at 2×10 6c/ml, in RPMI 1640 medium(Gibco BRL). Add compounds and preincubate with cells for 10 min beforeadding LPS (Calbiochem, Calif.) at 1 ug/ml for 5 hours. Collectsupematent and assay for TNFα production by standard sandwich ELISA (R&DSystems, Minneapolis, Minn.). Compound inhibition was determinedrelative to cells cultured with LPS alone.

Assay for Her-2 Sheddase Activity

A human breast cell cancer line BT474 (ATCC, Manassas, Va.), is seededat 2×10⁴ cells/well in 100 μL in a 96 well plate (Costar/Corning VWR,NJ) in RPMI 1640 media (In Vitrogen, Carlsbad, Calif.) containing 10%fetal bovine serum (Hyclone, Lenexa, Kans.), and incubated overnight at37° C., 5% CO₂. The following morning media is removed and fresh mediais added back at 100 μL/well. Compounds are added at appropriateconcentrations and the cells are incubated for 72 hour at 37° C., 5%CO₂. Supernatants are then removed and either tested immediately orstored at −20° C. until testing can be performed. Supernatants aretested at a 1/20 dilution for inhibition of Her-2 sheddase by commercialELISA (Oncogene Research, San Diego, Calif.)). Compound inhibition wasdetermined relative to cells cultured alone.

ADAM and MMP In Vitro Assays

Except for ADAM17 and MT1-MMP, all recombinant human MMPs and ADAMs wereobtained from R&D Systems (Minneapolis, Minn.). Their catalog numbersare as following: MMP1 (901-MP), MMP2 (902-MP), MMP3 (513-MP), MMP7(907-MP), MMP8 (908-MP), MMP9 (911-MP), MMP10 (910-MP), MMP12 (919-MP),MMP13 (511-MM), ADAM9 (939-AD), and ADAM10 (936-AD). MT1-MMP wasobtained from US Biological (Swampscott, Mass.) with a catalog number ofM2429. Porcine ADAM17 was purified in house from porcine spleen.

Fluorogenic Peptide substrate, (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Ala-Arg-NH₂,was obtained from R&D Systems with a catalog number of ES001. It wasused as substrate for MMP1, MMP2, MMP7, MMP8, MMP9, MMP12, MMP13, andMT1-MMP assays. Fluorogenic Peptide substrate, (7-methoxycoumarin-4-yl)acetyl-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(2,4-dinitrophenyl)-NH₂,was obtained from R&D Systems with a catalog number of ES002. It wasused as substrate for MMP3 and MMP10 assays. Fluorogenic Peptidesubstrate,(7-methoxycourmarin-4-yl)-acetyl-Pro-Leu-Ala-Gln-Ala-Val-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Arg-Ser-Ser-Ser-Arg-NH₂,was obtained from R&D Systems with a catalog number of ES003. It wasused as substrate for ADAM9, ADAM10, and ADAM17 assays.

Assay Buffer Conditions: In general, assay buffer condition was chosenbased on obtaining optimal enzymatic activities. The specific assaybuffer conditions are summarized as following. For MMP1, MMP2, MMP3,MMP7, and MMP12, the assay buffer contains 50 mM Tricine, 10 mM NaCl, 10mM CaCl₂, 1.0 mM ZnCl₂, pH 7.4. For MMP8 and MMP13, the assay buffercontains 50 mM Tricine, 10 mM NaCl, 10 mM CaCl₂, 1.0 mM ZnCl₂, 0.001%Brij35, pH 7.4. For MMP9 and MMP10, the assay buffer contains 50 mMTris-HCl, 150 mM NaCl, 10 mM CaCl₂, 0.001% Brij35, pH 7.5. For MT1-MMP,the assay buffer contains 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl₂,0.001 Brij35, pH 7.5. For ADAM9, the assay buffer contains 25 mM Tris,2.5 μM ZnCl₂, and 0.001% Brij35, 0.1 mg/mL BSA, pH 9.0. For ADAM10, theassay buffer contains 25 mM Tris, 2.5 μM ZnCl₂, and 0.005% Brij35, pH9.0. For ADAM17, the assay buffer contains 25 mM Tris, 2.5 μM ZnCl₂, and0.001% Brij35, pH 9.0.

To activate MMP enzymes, 10 or 20 μg of lyophilized Pro-MMPs weredissolved in 100 μL of water. 100 mM p-aminophenylmercuric acetate(APMA) stock in DMSO was added to Pro-MMPs to give 1.0 mM finalconcentration. Pro-MMPs were incubated with APMA at 37° C. for a periodtime specified below. For MMP1, MMP7, and MMP8, the incubation time was1 hour. For MMP10 and MMP13, the incubation time was 2 hours. For MMP3and MMP9, the incubation time was 24 hours.

In general, 5 mM compound stock was prepared in DMSO. 2-Fold serialdilution starting with a specific concentration was performed to givethe compound plate. 1.0 μL of compound in DMSO was transferred fromcompound plate to the assay plate. Enzyme solution was prepared in assaybuffer with a concentration specified below. Substrate solution wasprepared in assay buffer with a concentration of 20 μM. 50 μL of enzymesolution was added to the assay plate. The assay plate was incubated for5 minutes. 50 μL of substrate solution was then added to the assayplate. Protect the plate from the light and incubate the reaction atroom temperature or 37° C. for a period of time specified below. Thereaction was stopped by adding 10 μL of 500 mM EDTA solution. The platewas read on a plate reader with excitation of 320 nm and emission of 405nm. Percentage of inhibition was calculated for each concentration andIC50 value was generated from curve fitting. Specific conditions foreach assay are as following: MMP1 enzyme concentration 1000 ng/mL, roomtemperature, 1 hour incubation; MMP2 enzyme concentration 200 ng/mL,room temperature, 1 hour incubation; MMP3 enzyme concentration 1000ng/mL, room temperature 1 hour incubation; MMP7 enzyme concentration 100ng/mL, room temperature 1 hour incubation; MMP8 enzyme concentration 500ng/mL, room temperature, 2 hours incubation; MMP9 enzyme concentration100 ng/mL, room temperature, 1 hour incubation; MMP10 enzymeconcentration 1000 ng/mL, room temperature, 2 hours incubation; MMP12enzyme concentration 200 ng/mL, room temperature, 1 hour incubation;MMP13 enzyme concentration 200 ng/mL, room temperature, 1.5 hoursincubation; MT1-MMP enzyme concentration 200 ng/mL, room temperature, 1hour incubation; ADAM9 enzyme concentration 4000 ng/mL, incubated at 37°C. 6 hours; ADAM10 enzyme concentration 700 ng/mL, incubated at 37° C. 6hours; ADAM17 enzyme concentration 600 ng/mL, incubated at 37° C. 1hour.

MMP2 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 μL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 10 ng/50 μL. Substrate solution was prepared in assaybuffer with a concentration of 20 μM. 50 μL of enzyme solution was addedto the assay plate. The assay plate was incubated for 5 minutes. 50 μLof substrate solution was then added to the assay plate. Protect theplate from the light and incubate the reaction at room temperature for 1hour. The reaction was stopped by adding 10 μL of 500 mM EDTA solution.Read the plate on a plate reader with excitation of 320 nm and emissionof 405 nm.

MMP3 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 μL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 50 ng/50 μL. Substrate solution was prepared in assaybuffer with a concentration of 20 μM. 50 μL of enzyme solution was addedto the assay plate. The assay plate was incubated for 5 minutes. Add 10μL of 500 mM EDTA to background wells. 50 μL of substrate solution wasthen added to the assay plate. Protect the plate from the light andincubate the reaction at room temperature for 1 hour. The reaction wasstopped by adding 10 μL of 500 mM EDTA solution. Read the plate on aplate reader with excitation of 320 nm and emission of 405 nm.

MMP12 Assay

5 mM compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500μM. 1 μL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 10 ng/50 μL. Substrate ((7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Ala-Arg-NH₂)solution was prepared in assay buffer with a concentration of 20 μM. 50μL of enzyme solution was added to the assay plate. The assay plate wasincubated for 5 minutes. Add 10 μL of 500 mM EDTA in the backgroundwell. 50 μL of substrate solution was then added to the assay plate.Protect the plate from the light and incubate the reaction at roomtemperature for 1 hour. The reaction was stopped by adding 10 μL of 500mM EDTA solution. Read the plate on a plate reader with excitation of320 nm and emission of 405 nm.

ADAM10 Assay

5 mM Compound stock was prepared in DMSO. Compound plate was prepared by2-fold dilution for 11-point curve, with highest concentration of 500uM. 1 μL of compound in DMSO was transferred from compound plate to theassay plate. Enzyme solution was prepared in assay buffer with aconcentration of 100 ng/50 μL. Substrate((7-methoxycourmarin-4-yl)-acetyl-Pro-Leu-Ala-Gln-Ala-Val-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Arg-Ser-Ser-Ser-Arg-NH₂)solution was prepared in assay buffer with a concentration of 20 μM. 50μL of enzyme solution was added to the assay plate. The assay plate wasincubated for 5 minutes. 50 μL of substrate solution was then added tothe assay plate. The plate was protected from light and incubated at 37°C. for 4 hours. The reaction was stopped by adding 10 uL of 500 mM EDTAsolution. The plate was read on a plate reader with excitation of 320 nmand emission of 405 nm.

ADAM15 Assay

ADAM15 can be assayed in a similar fashion to ADAM10 (see, e.g., Fourieet al., J Biol Chem. 2003, 278(33), 30469-77). In brief, a fluorescencequenched peptide substrate is made by labeling one terminus with afluorescent dye and the other terminus with a quencher dye. Cleavage ofthe peptide by ADAM15 can be measured by the increase in fluorescenceintensity as a result of the decrease in proximity of the quencher dyeto the fluorescent dye.

Compound Activity

The compounds of the present invention have IC50 values in the range ofabout 5 nM to about 10 μM for target inhibition when tested by at leastone of the above in vitro assays.

In Vivo Assay

To measure the antineoplastic activity of metalloprotease inhibitors,both estrogen dependent (MCF-7 and BT-474) and independent (MDA-MB-435)human breast cancer cell lines were used in immune compromised mouse(BALB/c nude and SCID/bg) xenograft experiments. The BT-474 tumors werefrom a subclone of the parental BT-474 cells from ATCC (BT-474-SCl) thatwere selected based on their increased tumor take and growth rates butare referred to herein as BT-474 for simplicity sake. In the BT-474 andMCF-7 tumor models, slow-release estrogen pellets (Innovative Researchof America) were inserted subcutaneously (s.c.) into the flank of eachmouse 24 hours prior to tumor cell inoculation. For all models, theindicated number of cells is combined with BD Matrigel™ at a 1:1 ratioimmediately prior to implantation. The day after estrogen pelletimplantation, 2×10⁷ BT-474 cells were injected s.c. into the upper flankof each mouse. MCF-7 tumors were generated by s.c. implantation of 5×10⁶cells injected in similar fashion. For the MDA-MB-435 tumor cells, 2×10⁶cells were inject s.c. into the flank of BALB/c nude mice. For allmodels, tumors were measured on a weekly basis and their volumescalculated using the formula [volume=(length×width²)÷2]. Once the meantumor volume of the required number of mice reached the desired size(usually >150 mm³), they were randomized into treatment groups usuallycontaining between 6 and 10 mice. Animals were then treated with testcompound or vehicle by mini-osmotic pump implated i.p. or s.c. for 7 to28 days to achieve the desired compound exposure—controlled by alteringthe pump flow rate and/or the concentration of compound inside thepumps. Tumor size and body weights (a measure of animal health) weremonitored weekly. Blood samples were also drawn while the osmotic pumpswere functional and plasma was separated (by centrifugation) and storedat −80° C. for later pharmacokinetic analysis.

Methods of Treatment, Dosages and Formulations

The compounds of the invention can be administered to a mammal, such asa human, but can also be administered to other mammals such as an animalin need of veterinary treatment, e.g., domestic animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike). The mammal treated in the methods of the invention is a mammal,male or female, in whom modulation of matrix metalloprotease activity isdesired. The term modulation is intended to encompass antagonism,agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician.

The compounds of the invention are administered in therapeuticallyeffective amounts to treat a disease for example such as rheumatoidarthritis. A therapeutically effective amount of a compound is thatamount which results in the inhibition of one or more of the processesmediated by metalloproteases in a subject with a disease associated withaberrant metalloprotease activity. Alternatively, a therapeuticallyeffective amount of a compound is the quantity required to achieve adesired therapeutic and/or prophylactic effect, such as an amount whichresults in the prevention of or a decrease in the symptoms associatedwith a disease associated with aberrant metalloprotease activity.

The present invention provides a method for treating a diseaseassociated with unwanted metalloprotease activity in a mammaliansubject. In some embodiments, the unwanted metalloprotease activity isassociated with arthritis, cancer (such as breast cancer, ovariancancer, prostate cancer, non-small cell lung cancer, colon cancer,gastric cancer, pancreatic cancer, glioma, and the like), cardiovasculardisorders, skin disorders, inflammation or allergic conditions. Infurther embodiments, the present invention provides a method ofinhibiting pathological changes mediated by elevated levels ofmetalloproteases in mammals.

The compounds herein are useful in treating diseases, pathologicconditions and disorders associated with metalloprotease activity suchas by modulation (e.g., inhibition or antagonism) of metalloproteasesincluding matrix metalloproteases (MMPs), ADAMs, ADAM-TSs, and sheddaseswhich can pathologically involve aberrant extracellular matrixdegradation, shedding of cell surface protein ectodomains, and/or TNFsynthesis. In further embodiments, the compounds of the inventionmodulate matrix metalloproteases (e.g., MMP12, MMP14, MMP3, MMP2, orMMP9), members of the ADAMs family of enzymes including TNFα-convertase, ADAM10, ADAM15, ADAM17 and sheddases such as Her-2sheddase, heparin-binding EGF sheddase. The compounds of the inventioncan modulate activity of ADAMs which are believed responsible for therelease or shedding of soluble receptors (for example, CD30 andreceptors for TNF), adhesion molecules (for example, L-selectin, ICAM-1,fibronectin), growth factors and cytokines (for example Fas ligand,TGF-α, EGF, HB-EGF, SCF IL-6, IL-1, TSH and M-CSF), and growth factorreceptors (for example EGFR family members, such as Her-2 and Her-4)which have been implicated in the pathogenesis of different types ofcancer, including breast cancer, ovarian cancer, prostate cancer,non-small cell lung cancer, colon cancer, gastric cancer, pancreaticcancer and glioma. Accordingly, the compounds of the invention can beuseful in the treatment of diseases and disorders related to activity ofany of the above-named targets.

Diseases or conditions of human or other species which can be treatedwith the metalloprotease modulators of the invention, include, but arenot limited to: inflammatory or allergic diseases and conditions,including respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; neoplastic diseases suchas breast cancer and cancers with leukocyte infiltration of the skin ororgans. Other diseases or conditions in which undesirable inflammatoryresponses are to be inhibited can be treated, including, but not limitedto, reperfusion injury, atherosclerosis, certain hematologicmalignancies, cytokine-induced toxicity (e.g., septic shock, endotoxicshock), polymyositis, and dermatomyositis.

The compounds represented of the invention can be administered in suchoral dosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the metabolic stability, rate of excretion, drugcombination, and length of action of that compound the species, age,sex, health, medical condition, and weight of the recipient; the natureand extent of the symptoms; the kind of concurrent treatment; thefrequency of treatment; the specific route of administration, the renaland hepatic function of the patient, and the desired effect. A physicianor veterinarian can determine and prescribe the effective amount of thedrug required to prevent, counter, or arrest the progress of thespecific disorder for which treatment is necessary.

Generally, the daily oral dosage of each active ingredient, when usedfor the indicated effects, will range between about 0.0001 to 1000 mg/kgof body weight, preferably between about 0.001 to 100 mg/kg of bodyweight per day, and most preferably between about 0.1 to 20 mg/kg/day.For intravenous use, the most preferred doses will range from about 0.1to about 10 mg/kg/minute during a constant rate infusion. For oraladministration, the compositions are preferably provided in the form oftablets containing 1.0 to 1000 milligrams of the active ingredient,particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0,200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

The compounds of the instant invention can also be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using transdermal skin patches. When administered inthe form of a transdermal delivery system, the dosageadministration-will, of course, be continuous rather than intermittentthroughout the dosage regimen.

The compounds of the invention are typically administered in admixturewith suitable pharmaceutical diluents, excipients, or carriers(collectively referred to herein as pharmaceutical carriers) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.For oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Additionally,when desired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor 3-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be provided to a patientin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or poly-ethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, and crosslinked oramphipathic block copolymers of hydrogels.

Dosage forms for the compounds of the invention suitable foradministration may contain from about 0.1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

Gelatin capsules can also be used as dosage forms and may contain theactive ingredient and powdered carriers, such as lactose, starch,cellulose derivatives, magnesium stearate, stearic acid, and the like.Similar diluents can be used to make compressed tablets. Both tabletsand capsules can be manufactured as sustained release products toprovide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

When using liquid dosage forms for oral administration they can containcoloring and flavoring to increase patient acceptance.

Generally, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, Mack Publishing Company, a standardreference text in the field of pharmacology.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed. Asused herein, topical application is also meant to include the use ofmouth washes and gargles.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds which areusually applied in the treatment of the above mentioned pathologicalconditions.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 50 milligrams of powderedactive ingredient, 100 milligrams of lactose, 25 milligrams ofcellulose, and 3 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 75 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 75 milligrams of active ingredient, 0.15 milligrams of colloidalsilicon dioxide, 4 milligrams of magnesium stearate, 250 milligrams ofmicrocrystalline cellulose, 9 milligrams of starch and 75 milligrams oflactose. Appropriate coatings well known to one skilled in the art maybe applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.0% by weight of active ingredient in 8% by volumepropylene glycol and water. The solution should be made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 75 mg of finely divided active ingredient, 150 mg ofsodium carboxymethyl cellulose, 3.75 mg of sodium benzoate, 0.75 g ofsorbitol solution, U.S.P., and 0.015 mL of vanillin.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

While the many forms of the invention herein disclosed constitutepresently preferred embodiments, many others are possible and furtherdetails of the preferred embodiments and other possible embodiments arenot to be construed as limitations. It is understood that the terms usedherein are merely descriptive rather than limiting and that variouschanges many equivalents may be made without departing from the spiritor scope of the claimed invention.

What is claimed is:
 1. A method for treating a disease associated withunwanted ADAM10, ADAM15, or ADAM17 activity in a mammalian subject, themethod comprising administering to said mammal in need thereof atherapeutically effective amount of a compound which is methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate,or a pharmaceutically acceptable salt thereof, wherein the disease isselected from breast cancer, ovarian cancer, prostate cancer, non-smallcell lung cancer, colon cancer, gastric cancer, pancreatic cancer, andglioma.
 2. The method of claim 1, wherein the disease is associated withunwanted ADAM10 activity.
 3. The method of claim 1, wherein the diseaseis associated with unwanted ADAM15 activity.
 4. The method of claim 1,wherein the disease is associated with unwanted ADAM17 activity.
 5. Themethod of claim 1, wherein the disease is glioma.
 6. The method of claim1, wherein the compound methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateis administered.
 7. The method of claim 2, wherein the compound methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateis administered.
 8. The method of claim 3, wherein the compound methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateis administered.
 9. The method of claim 4, wherein the compound methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateis administered.
 10. The method of claim 5, wherein the compound methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylateis administered.